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Intramolecular alkylation of α,β-unsaturated ketones, an approach to the synthesis of zizaane type sesquiterpenoids… Zbozny, Michael 1978

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INTRAMOLECULAR ALKYLATION OF a,3-UNSATURATED KETONES, AN APPROACH TO THE SYNTHESIS OF ZIZAANE TYPE SESQUITERPENOIDS AND THE TOTAL SYNTHESIS OF (±) ISOLONGIFOLENE by MICHAEL ZBOZNY B.Sc, University of Guelph, 1969 M.Sc, University of Guelph, 1972 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA May, 19 7 8 (c) Michael Zbozny, 1978 In presenting th i s thes is in p a r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary shal l make it f ree l y ava i lab le for reference and study. I fur ther agree that permission for extensive copying of th is thes is for scho la r l y purposes may be granted by the Head of my Department or by his representat ives . It is understood that copying or pub l i ca t ion of th is thes is for f i n a n c i a l gain sha l l not be allowed without my wri t ten permission. Department of The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 ABSTRACT In the f i r s t p a r t of t h i s t h e s i s an i n t r a m o l e c u l a r a l k y l a t i o n study i n v o l v i n g 4a-(3-chloropropy1)-4,4a,5,6,7,8— hexahydro-2-(3H) -napthalenone (77a) , 4 a- ( 3-iodopropy 1) - 4,4a,5,6,7, 8,-hexahydro-2(3H)-napthalenone(77b) and 4a-(mesylate m e t h y l ) — 4,4a,5,6,7,8,hexahydro-2(3H)-napthalenone(95) i s d e s c r i b e d . B i c y c l i c a, ^ - u n s a t u r a t e d ketones (77a), (77b) and (95) were prepared and t h e i r c y c l i z a t i o n s v i a i n t r a m o l e c u l a r a l k y l a t i o n under a v a r i e t y o f r e a c t i o n c o n d i t i o n s was i n v e s t i g a t e d . In the case of ketone (77a) h i g h s e l e c t i v i t y f o r a or d ' - a l k y l a -t i o n was a c h i e v e d by v a r y i n g c e r t a i n r e a c t i o n parameters. The r e a c t i o n parameters s t u d i e d were s o l v e n t , base, complexing agent and l e a v i n g group. The a c t i o n of potassium t - b u t o x i d e i n t - b u t y l a l c o h o l on o c t a l o n e (77a) a f f o r d e d ketone (90) as the major product and ketone (91) as the minor product. A change i n the s o l v e n t system to a 60/40 mixture of THF/t-BuOH combined w i t h the a d d i -t i o n of 18-crown-6 a f f o r d e d s e l e c t i v e l y ketone (90). The a c t i o n of potassium t - b u t o x i d e i n t - b u t y l a l c o h o l on o c t a l o n e (77b) however, a f f o r d e d the ketone (91) e x c l u s i v e l y . E x c l u s i v e f o r m a t i o n of ketone (91) was a l s o achieved by the a c t i o n of l i t h i u m d i i s o p r o p y l a m i d e i n THF on ketone (77a). A t no time was ketone (92) d e t e c t e d . B i c y c l i c ketone (95) having a mesylate methyl group a t the angular p o s i t i o n was s u b j e c t e d t o a number o f r e a c t i o n c o n d i -t i o n s . The p o s i t i o n of a l k y l a t i o n was found to be dependent i i i on solvent and the presence of 18-crown-6. The action of lithium t-butoxide or potassium t-butoxide i n t-butyl alcohol or THF on ketone (95) afforded exclusively ketone (66). The ketone (95) i n HMPA, with or without 18-crown-6, however afforded ketone (104) as the major product and ketone (66) as the minor product. Ketone (103) was not detected. In the second part of t h i s thesis a 15-step synthesis of (±) isolongifolene (114) from 4a-(carbomethoxy)-4a,4,5,6,7,8— hexahydro-2-(3H) -napthalenone (97) i s described. A l k y l a t i o n with methyl iodide of (97) afforded the dimethylated octalone (146). Octalone (146) was transformed into octalone (147) v i a a Wittig reaction using methylenetriphenylphosphorane. Diene (147) was hydroborated using disiamylborane i n THF and the resultant mixture of alcohols (148) and (149) was acetylated with acetic anhydride and pyridine to a f f o r d acetates (153) and (154). The l a t t e r mixture was a l l y l i c a l l y oxidized by the action of N — bromosuccinimide i n dioxane i n the presence of l i g h t to y i e l d keto acetates (155) and (156). Decarbomethoxylation of the keto acetates followed by k e t a l i z a t i o n of resultant mixture afforded ketal acetate (160). Lithium aluminum hydride reduc-t i o n of (160) followed by t o s y l a t i o n of the resultant alcohol (161) afforded ketal tosylate (162). Acid hydrolysis of (162) followed by intramolecular a l k y l a t i o n of the resultant keto tosylate (163) afforded the t r i c y c l i c octalone (165). Dehydro-genation of the l a t t e r using DDQ yielded dienone (166) which when treated with l i t h i u m dimethylcuprate i n ether afforded octalone (167). Treatment of (167) with pyridinium hydrobromide i v perbromide followed by dehydrobromination of the resultant crude bromide (168) afforded the cross conjugated ketone (169). The l a t t e r was converted into octalone (124) v i a a methyl cuprate reaction. Octalone (124) was not converted into (±) isolongifolene since t h i s transformation had already been reported. Dienone (166) was converted into a, B-unsaturated keto n i t r i l e (172) by the action of d i e t h y l aluminum cyanide on the former. This transformation was to eventually provide an entry into the zizaane class of sesquiterpenoids. V . TABLE OF CONTENTS Page PART I INTRODUCTION I. INTERMOLECULAR ALKYLATION OF a, 3-UNSATURATED KETONES . . . 1 (A) GENERAL COMMENTS . . . 1 (B) ALKYLATION OF ENOLATE ANIONS FORMED UNDER KINETICALLY CONTROLLED DEPROTONATION . . . 6 (C) ALKYLATION OF ENOLATE ANIONS FORMED UNDER THERMODYNAMICALLY CONTROLLED DEPROTONATION 9 (D) METHODS FOR THE OVERALL MONOALKYLATION OF a, 3-UNSATURATED KETONES AT THE POSITION . . . 13 II. INTRAMOLECULAR ALKYLATION OF KETONES . . . 20 (A) SATURATED KETONES . . . 20 (B) a,3-UNSATURATED KETONES AND ALDEHYDES . . . 24 III. THE PROBLEM . . . 30 DISCUSSION I. PREPARATION OF 4a-(3-CHLOROPROPYL)-4,4a,5,6,7,8 — HEXAHYDRO-2-{3H) -NAPTHALENONE (77a) and 4a- (3—r IODOPROPYL) -4, 4a,5, 6, 7, 8-HEXAHYDRO-2-(3H) — NAPTHALENONE(77b) . . . 31 II. INTRAMOLECULAR ALKYLATION STUDY . . . 41 (A) GENERAL CONSIDERATIONS . . . 41 (B) INTRAMOLECULAR ALKYLATION INVOLVING 4a— (3-CHLOROPROPYL)-4a,4,5,6,7,8-HEXAHYDRO— 2-(3H)-NAPTHALENONE (7 7a) . . . 44 1. General . . . 44 2. Effect of Solvent . . . 46 3. Effect of Base . . . 47 4. Effect of Complexing Agent . . . 49 5. Synthetic Application . . . 49 (C) INTRAMOLECULAR ALKYLATION INVOLVING 4a— (3-IODOPROPYL)- 4a,4,5,6,7,8-HEXAHYDRO— 2-{3H)-NAPTHALENONE (77b) . . . 51 (D) SUMMARY OF INTRAMOLECULAR ALKYLATION STUDY 54 (E) STRUCTURAL ASSIGNMENT OF ALKYLATION PRODUCTS . . . 55 v i Page II I . PREPARATION OF 4a-(MESYLATE METHYL)-4a,4,5,6,7,8— HEXAHYDRO- 2-{ 3H) -NAPTHALENONE (95) . . . 58 IV. INTRAMOLECULAR ALKYLATION STUDY INVOLVING 4 a — (MESYLATE METHYL)-4a,4,5,6,7,8-HEXAHYDRO-2(3H) — NAPTHALENONE (95) . . . 64 (A) GENERAL COMMENTS . . . 64 (B) INTRAMOLECULAR ALKYLATION OF MESYLATE (95) 6 7 1. General 67 2.. E f f e c t of Solvent . . . 69 3. E f f e c t of Base . . . 74 4. E f f e c t of Complexing Agent . . . 77 5. Synthetic Application . . . 78 (C) STRUCTURAL ASSIGNMENT OF ALKYLATION PRODUCT 79 EXPERIMENTAL 82 PART II SYNTHETIC STUDIES ON ZIZAANE-TYPE SESQUITERPENOIDS AND THE TOTAL SYNTHESIS OF (±)-ISOLONGIFOLENE INTRODUCTION 105 . I. GENERAL REMARKS . . . 105 I I . STRUCTURE AND PREVIOUS SYNTHESIS OF ( ± ) — ISOLONGIFOLENE . . . 108 I I I . STRUCTURE AND PREVIOUS SYNTHESIS OF SOME ZIZAANE— TYPE OF SESQUITERPENOIDS . . . I l l DISCUSSION 126 I. GENERAL APPROACH . . . 126 II . TOTAL SYNTHESIS OF (±) ISOLONGIFOLENE . . . 133 I I I . AN APPROACH TO THE ZIZAANE CLASS OF SESQUITERPENES 153 EXPERIMENTAL 156 REFERENCES 174 LIST OF TABLES Table I T a b l e I I Page 52 75 v i i i ACKNOWLEDGEMENT I t i s a w e l l known f a c t t h a t the w r i t i n g of a t h e s i s r e q u i r e s the h e l p of many people and I would l i k e to take t h i s o p p o r t u n i t y to thank the f o l l o w i n g persons f o r t h e i r c o n t r i b u t i o n s . I acknowledge the guidance and encouragement of Dr. Edward P i e r s . T h i s i s procedure. I am a l s o o b l i g e d to p r a i s e the p a t i e n c e he has endured and the understanding t h a t he has shown. T h i s r e c o g n i t i o n i s t r a d i t i o n a l . I must a l s o thank him f o r something more: namely'his p e r s o n a l i t y and the time he took to share i t w i t h me. I enjoyed i t . Ed, you make i t look easy. I am a l s o i n d e b t e d to the other members; both p a s t and p r e s e n t , of our r e s e a r c h group as w e l l as members o f Dr. Kutney's group f o r the many worthwhile d i s c u s s i o n s . S p e c i a thanks are due to D. Herbert and Dr. P.M. Worster. P a u l , f o r h i s advice and i n v a l u a b l e enthusiasm i n the e a r l y stages of my r e s e a r c h . And, Dave, f o r being c o n s i s t e n t w i t h h i s knowledge and concern throughout and f o r h i s p r o o f r e a d i n g . The Macmillan b r o t h e r s w i l l not be f o r g o t t e n . Dave, who s e t the c h a l l e n g e , and Chub who w i l l always be t h e r e . ix To Malcolm and David MacMlllan -1-INTRODUCTION I. INTERMOLECULAR ALKYLATION OF • a 3-UNSATURATED KETONES (A) GENERAL COMMENTS Sin c e the f o l l o w i n g p o r t i o n o f t h i s t h e s i s d e a l s p r i m a r i l y w i t h the i n t r a m o l e c u l a r a l k y l a t i o n of a number of a 3 - u n s a t u r a t e d ketones, i t i s p e r t i n e n t t o d i s c u s s i n g e n e r a l the a l k y l a t i o n o f a B-unsaturated ketones. G e n e r a l l y , the a l k y l a t i o n o f an a ( 8 - u n s a t u r a t e d ketone r e q u i r e s the i n i t i a l f o r m a t i o n o f a resonance s t a b i l i z e d d i e n o l a t e anion. T h i s i s u s u a l l y accomplished by t r e a t i n g the a 3-unsaturated ketone w i t h a s t r o n g base i n an a p p r o p r i a t e s o l v e n t . I t has been shown^" t h a t the a c t i o n of s t r o n g base on an a,$ -unsaturated ketone i n i t i a l l y forms the l e s s s t a b l e d i e n o l a t e anion (A), by the k i n e t i c a l l y c o n t r o l l e d a b s t r a c t i o n of an of p r o t o n . The process i s shown i n eq u a t i o n ( I ) . The f a t e of the d i e n o l a t e anion (A) w i l l depend on the r e a c t i o n c o n d i t i o n s and on the-nature o f the pa r e n t a,3-unsatur-ated ketone (1). D i e n o l a t e anion (A) can e i t h e r r e a c t w i t h the a l k y l a t i n g agent, to form a l k y l a t e d product, o r can, i n the -2-presence of a s u i t a b l e p r o t o n source, undergo proton t r a n s f e r and be conv e r t e d back t o the o r i g i n a l a,£-unsaturated ketone (see e quation ( 2 ) ) . (1) (A) (2) I f the r e a c t i o n c o n d i t i o n s are such t h a t a l k y l a t i o n i s f a s t e r than p r o t o n t r a n s f e r , (rate karate K_^) , then the a l k y -l a t e d p r o d u c t would be formed. A b s t r a c t i o n o f the gamma proton i n ketone (1) w i l l form the thermodynamically more s t a b l e d i e n o l a t e anion (B). The l a t t e r i s u s u a l l y a l k y l a t e d a t the a p o s i t i o n , i n i t i a l l y forming the 6 - a l k y l a t e d - £ yy-unsaturated 2 ketone (3) . The o v e r a l l p rocess i s shown i n equ a t i o n 3. R 1 (1) (3) .(3), -3-Ketone (3) may i s o m e r i z e to an «-alkyl-a , ^ -unsaturated ketone (7), v i a d i e n o l a t e anion (5), or undergo f u r t h e r a l k y l a -t i o n , a l s o v i a d i e n o l a t e anion (5), to form cc, a - d i a l k y l a t e d — g ,y^unsaturated ketone (6) . These r e a c t i o n s are o u t l i n e d below. U s u a l l y the l a t t e r process predominates g i v i n g as the major product the a / a - d i a l k y l a t e d - g ; y - u n s a t u r a t e d ketone (6). The l a t t e r p r o c e s s , l e a d i n g t o the formation of d i e n o l a t e anion (5), i s the predominant pathway because the a proton of the 3 ,^-un-saturated- ketone (3) i s k i n e t i e a l l y more a c i d i c than the y protons of e i t h e r the s t a r t i n g a,g-unsaturated ketone (1) o r the (6) (5) ' (7) a - a l k y l - a,3-unsaturated ketone (7). The i n t e r m e d i a t e (5) 2 then undergoes i r r e v e r s i b l e a l k y l a t i o n to form compound (6) . The o v e r a l l p rocess i s d e p i c t e d i n Scheme I. -4-R* R* R' R.' (6). (5) (7) R,R'=alkyl X =halide SCHEME I -5-From Scheme I i t i s clear that treatment of an a, g-unsatur-ated ketone with base and an a l k y l a t i n g reagent can lead to a complex mixture of products, including compounds of the type (2), (3), (6) and (7). R'R' (6) R' (7) Cl e a r l y , i t would be advantageous, from a synthetic point of view, to be able to control the type of product formed. In summary, the problems associated with the a l k y l a t i o n of a ^-unsat-urated ketone systems are three f o l d . F i r s t l y , how does one s e l e c t i v e l y form one of the two possible dienolate anions (A) or (B)? Secondly, how does one s e l e c t i v e l y a l k y late one of the two possible dienolate anions (A) or (B)? La s t l y , how does one stop the a l k y l a t i o n , of either dienolate anion (A) or dieno-late anion (B), at the monoalkylation stage? -6-(B) ALKYLATION OF ENOLATE ANIONS FORMED UNDER KINETICALLY CONTROLLED DEPROTONATION The f i r s t two problems mentioned above can be d i s -cussed t o g e t h e r s i n c e they are c l o s e l y r e l a t e d i n t h a t the a l -k y l a t i o n of a s p e c i f i c e n o l a t e anion f o l l o w s from the i n i t i a l g e n e r a t i o n of a s p e c i f i c e n o l a t e . That i s to say, once a s p e c i f i c e n o l a t e anion has been generated, one may then a l k y l a t e i t , pro-v i d e d of course t h a t the e n o l a t e anion has a s u f f i c i e n t l i f e -time. The f i r s t of these problems has been approached by con-s i d e r i n g e q u a t i o n (4) . I t has been shown^" t h a t treatment of an-a^,3"unsaturated ketone w i t h s t r o n g base w i l l e f f e c t the ab-s t r a c t i o n o f one ct proton t o form d i e n o l a t e anion (A). Con-t r o l l i n g the r e a c t i o n c o n d i t i o n s such t h a t r a t e ^ r a t e _ ^ or r a t e 0 would ensure the formation of the d i e n o l a t e anion (A). T h i s has been accomplished by employing l i t h i u m d i a l k y l a m i d e s as bases. To p r o l o n g the l i f e t i m e o f d i e n o l a t e anion (A) the r e a c --7-ti o n i s usually carried out i n an aprotic solvent and at low temperatures. By using a reactive a l k y l a t i n g agent s e l e c t i v e a l k y l a t i o n of the k i n e t i c a l l y preferred enolate can be achieved ( r a t e ^ r a t e ^) . Below are a few examples of a' a l k y l a t i o n of a^-unsaturated ketone systems. (8) (9) (10) Thus W. Reusch et a l ' found that treatment of pulegone (8) with lithiu m isopropylcyclohexylamide i n THF* at 0° followed by the addition of methyl iodide afforded the a-alkylated ketone (9) as the major product i n 56% y i e l d . The minor product, ketone (10), was the product of ff-alkylation. S i m i l a r i l y they found, that under the same conditions, cholest-4-ene-3-one (11) and 5,5-dimethylcyclohex-2-ene-l-one (12), gave dimethyl de-r i v a t i v e s (13) and (14), respectively, as the predominant products. Bucourt et a l ^ have shown that c/'alky l a t i o n can be achieved by using potassium t-butoxide as base and by working at low * Tetrahydrofuran - THF -8-(12) (14) temperatures (-70 ) i n an aprotic solvent. Thus, treatment of a THF solu t i o n of 17-methyl-19-nortestosterone-tetrahydropyranyl ether (15) and methyl iodide (1 equivalent) at -70°, with excess potassium t-butoxide i n THF f o r 1.5 hours, resulted i n the f o r -mation of the monomethylated nortestosterone (16). By employing (15) (16) more methyl iodide dimethylated product (17) was formed as the -9-major product. OTHP (17) Thus, i t has been p o s s i b l e t o generate and monoalkylate the k i n e t i c a l l y p r e f e r r e d l i t h i u m and potassium e n o l a t e anions by m o d i f y i n g the r e l a t i v e r a t e s of a l k y l a t i o n and i s o m e r i z a -t i o n of the i n i t i a l l y formed d i e n o l a t e anion. (C) ALKYLATION OF ENOLATE ANIONS FORMED UNDER THERMODYNAMICALLY CONTROLLED DEPROTONATION Formation o f the d i e n o l a t e anion (B), (thermody-n a m i c a l l y more s t a b l e than d i e n o l a t e anion (A)), i s accomplished under e q u i l i b r a t i n g c o n d i t i o n s u s i n g bases such as potassium t-butoxide i n a p r o t i c s o l v e n t such as t - b u t y l a l c o h o l . Under these c o n d i t i o n s 'dienolate anion (B) i s formed a t the expense of d i e n o l a t e anion (A): i . e . , the e q u i l i b r i u m i s allowed t o 2 be e s t a b l i s h e d i n favour of the d i e n o l a t e anion (B). T h e o r e t i -c a l l y , treatment o f the l a t t e r w i t h an a l k y l a t i n g agent c o u l d r e s u l t i n a l k y l a t i o n a t e i t h e r the alpha o r the gamma carbon atom. In p r a c t i c e , C - a l k y l a t i o n occurs predominantly at the^ -10-.(A) (1) (B) a.. carbon J the carbon bearing the highest e l ec t ron density ' , to form a ^y-unsaturated ketone (3). The i n i t i a l product (3) may be isomerized to an d-alkyl-a . ,6 -unsaturated ketone (7) or may undergo further a l k y l a t i o n to form the d i a l k y l a t e d product ketone (6). R'R 1 R 1 R 1 (6) (5) (7) -11-D i a l k y l a t i o n has often been the major process because the a -proton of ketone (3) i s more readi l y abstracted than the gamma protons of ketone (7) or the gamma protons of the i n i t i a l 2 6 st a r t i n g -unsaturated ketone (1) ' . Below are a few examples of the a l k y l a t i o n of the thermodynamically favoured enolate anions derived from a number of a^B -unsaturated ketones possessing a gamma proton. (19) (21) Thus, when excess methyl iodide i s added, at room temper-ature, to a solution of ei t h e r compound (18) or (19), which has been previously treated with potassium t-butoxide, i n t-butyl alcohol, the 4,4-dimethyl/f-3-one compounds (20) and 9 10 (21) were i s o l a t e d i n good y i e l d respectively ' Alpha a l k y l a t i o n i s the rule and gamma a l k y l a t i o n i s rare. -12-Below are two examples where gamma a l k y l a t i o n has been observed as the minor product. 0 0 0 7 5 - 8 0 % 1 0 - 1 5 % One example where gamma a l k y l a t i o n has been observed as the major product i s shown below. Snieckus et a l " ^ i n t h e i r synthesis of a pentacyclic a l k a l o i d model system employed as t h e i r key step the gamma a l k y l a t i o n of an a; 3-unsaturated , amide. Thus treatment of the a, 3-unsaturated amide (22) with 2 equivalents of n-butyl lithium i n TMEDA* and ethyl bromide afforded the gamma alkylated a, 3 -unsaturated amide (23). *TMEDA - Tetramethylenediamine -13-(D) METHODS FOR THE OVERALL MONOALKYLATION OF a,e-UNSATURATED KETONES AT THE a POSITION Thus f a r I have d i s c u s s e d the a l k y l a t i o n o f e n o l a t e anions formed under k i n e t i c a l l y c o n t r o l l e d d e p r o t o n a t i o n c o n d i -t i o n s as w e l l as the a l k y l a t i o n o f e n o l a t e anions formed under thermodynamically c o n t r o l l e d d e p r o t o n a t i o n c o n d i t i o n s . The t h i r d problem concerns the o v e r a l l m o n o a l k y l a t i o n o f ot, 8 -unsatur-ated ketones a t the a - p o s i t i o n . P i c t o r a l l y , the o v e r a l l t r a n s f o r m a t i o n r e q u i r e d i s shown i n equation (5). Stork has s o l v e d t h i s problem by making use o f metalloene-amines. The o v e r a l l p r o c e s s i s shown below. The a.B-unsatur--14-ated ketone to be monoalkylated is first transformed into an N-alkylimine derivative. More specifically, treatment of 10— methyl- A 1 '9-2-octalone (24) with excess cyclohexylamine in re-fluxing toluene containing a catalytic amount of p-toluenesulfonic acid afforded, in quantitative yield, the N-cyclohexylimine (25). A THF solution of imine (25) was allowed to react, under an atmosphere of nitrogen, with slightly less than one equivalent (28) (29) of lithium diisopropylamide. After refluxing for 8 hours an ex-cess of methyl iodide in THF was added and reflux was continued an additional overnight period. The resulting crude monoalky-lated imine was hydrolyzed with hot aqueous sodium acetate-acetic acid-water (1:2:2) for four hours. Isolation afforded a 95% recovery consisting of about 90% monoalkylated a;£-unsatur-ated ketone (28) and 10% of the starting unalkylated c t j g-un-saturated ketone (24) . -15-S i m i l a r i l y , isophorone-N,N-dimethy1 hydrazone (29) when treated with one equivalent of sodium hydride i n THF containing 10% hexamethylphosphoramide (HMPA) followed by reaction with 1-iodobutane (3 hrs, room temperature) and hydrolysis with hot 6N HCl (1 hr) gave n-butylisophorone (30) i n 70% y i e l d . The reaction of a l k y l Grignard reagents with N,N-dimethyl-hydrazones of a,3-epoxyketones has also been f r u i t f u l i n accom-p l i s h i n g o v e r a l l alpha monoalkylation of a, g -unsaturated ketones, 15 The secruence i s shown i n 31—>32. 0 (31) I N / \ * H N OH -16-To i l l u s t r a t e the f e a s i b i l i t y of the above sequence a detailed account using isophorone as substrate follows. (34) Thus, isophorone oxide (33), made by standard methods from isophorone, was allowed to react with 2 eq. of N,N-dimethyl-hydrazine and 0.5 eq of proprionic acid i n ethyl acetate at 0°. After f o r t y minutes the reaction mixture was treated with 10% aqueous sodium carbonate and the N,N-dimethylhydrazone (34), as a 1:1 mixture of syn and anti isomers, was i s o l a t e d i n 95% y i e l d . When the l a t t e r mixture was treated with 1.5 equiva-lents of phenylmagnesium bromide (THF, ^ room temperature, 1.5 hours), and the resultant crude product was hydrolyzed with 3N HCl i n 50% aqueous ethyl alcohol for 1 hour, 2-phenyl i s o -phorone (35) was obtained i n 77% y i e l d . Synthesis of (35), (R=methyl, but y l , and 3-methoxyphenethyl) was accomplished i n y i e l d s of 63, 65 and 61% respectively by using the proper Grignard reagent. -17-R=Phenyl, Methyl, B u t y l , 3-Methoxy Phenethyl (35) Another approach to the problem of m o n o a l k y l a t i o n o f ct^ p -unsaturated ketones worthy of mention has been developed by Corey e t a l ^ . The methodology i n v o l v e d i s shown below. OH ( C H 3 ) 2 C u N I "0 0 -/ C H ^ 2 C U 11 0 - 0 OH H0> -18-To i l l u s t r a t e the f e a s i b i l i t y of the above proposed scheme 16 Corey et a l converted 2,3-epoxycyclohexanone into t r a n s - 3 — hydroxy-2-methylcyclohexanone i n the following manner. Oxime (36) was obtained from the corresponding ketone by treatment of the l a t t e r with 1.1 equivalents of hydroxylamine hydrochloride and 2.2 equivalents of sodium acetate i n methanol at 0 ° c for 30 minutes. The oxime (36) i n ether was then added to f i v e equivalents of l i t h i u m dimethylcuprate at 25°C (1.25 hours) and the reaction was quenched below -25 °c with cold 10% acetic acid i n ether. Crude oxime (37). i n THF was treated with 2 equivalents N-OH . N-OH (38a) (38) of aqueous titanium t r i c h l o r i d e and 12 equivalents of ammon-ium acetate at 0 ° c for one hour. Evaporation of the solvent gave trans-3-hydroxy-2-methylcyclohexanone (38) i n 90% y i e l d as a colourless o i l of 90-95% puri t y . I t should be noted that compound (38) (and s i m i l a r 6-hydroxy ketones) i s ; i n general, rather unstable and e a s i l y dehydrated to the a, B -unsaturated ketone (38a^. Thus, o v e r a l l monoalkylation of an .a B —unsatur-ated ketone has been achieved. -19-One f i n a l example of monoalkylation of an a 3 -unsaturated ketone, involves the monomethylation of the morpholine enamine 19 17 derived from A '• -octalone-2. Thus, treatment of (39) with one equivalent of methyl iodide for twenty hours i n r e f l u x i n g dioxane gave the crude monoalky-lated enamine (40). Hydrolysis of-the l a t t e r with sodium acetate-acetic acid-water (reflux 4 hours) yielded a mixture of ketones (41) and (42). The g y -unsaturated ketone (41) was converted into the a ;3 -unsaturated ketone (42) by treatment of the former with 4% methanolic potassium hydroxide. -20-I I . INTRAMOLECULAR ALKYLATION OF KETONES (A) SATURATED KETONES Since t h i s thesis i s mainly concerned with the i n t r a -molecular a l k y l a t i o n of a /3-unsaturated ketones i t i s deemed appropriate at t h i s time to discuss, i n general, the i n t r a -molecular a l k y l a t i o n of a?3 -unsaturated ketones as well as the intramolecular a l k y l a t i o n of saturated ketones. The general theory i s as follows. I f the anionic carbon atom (marked (*)) of an enolate and the leaving group to be displaced (marked (x)) are separated by two or more carbons, the product w i l l be c y c l i c (see equa-tio n 6). The value of n determines the rin g size and, i n general, the r e l a t i v e rates of ring closure, to form various ri n g s i z e s , i s 3^> 5^>6)7^4, 8/> larger rings or intermolecular 2 reactions . Because of the very high rate of formation of three membered rings, cyclopropyl compounds can be successfully synthesised using very mild reaction conditions. However, ease 18 of ring formation i s not synonymous with ring s t a b i l i t y -21-Although the energy r e q u i r e d f o r r i n g c l o s u r e might be ex-pected t o r e f l e c t the s t a b i l i t y o f the product o t h e r f a c t o r s must be c o n s i d e r e d . One important f a c t o r which must be c o n s i -dered i s the p r o b a b i l i t y of the r e a c t i n g s i t e s approaching each o t h e r . As the r i n g s i z e i n c r e a s e s the p r o b a b i l i t y o f c y c l i z a -t i o n d e creases. O v e r a l l , ease o f formation i s r e l a t i v e l y high f o r t h ree membered r i n g s because the three atoms are n e c e s s a r i l y i n the optimum p o s i t i o n f o r r i n g c l o s u r e . However, once formed, the i n i t i a l p roducts may be capable o f r e a c t i n g w i t h the i n i -t i a l l y formed anion to g i v e a c y c l i c compounds as shown below. 19 ROOC WOC v C H „ — B r ' CH 2 Br B a s e COOR COOR COOR 'COOR COOR CH 00R COOR H -C-COOR f (CH' ) ~ I H - C-COOR l COOR I n t r a m o l e c u l a r a l k y l a t i o n s have found a p p l i c a t i o n f o r the s y n t h e s i s o f a v a r i e t y o f p o l y c y c l i c compounds. The l i t e r a t u r e p r o v i d e s many examples where i n t r a m o l e c u l a r a l k y l a t i o n s have been the c r u c i a l step i n the s y n t h e t i c d e sign l e a d i n g t o the formation o f carbon frameworks as v a r i e d as a t i s i n e (43) and (+)-copacamphor (44). -22-\ .o ' N H (44) (43) Although i t i s not possible to be exhaustive i n t h i s d i s -cussion, i t i s perhaps appropriate to present a few s p e c i f i c examples of intramolecular alkylations of saturated ketones. Examples of the l a t t e r can be found i n the synthesis of most classes of natural products such as a l k a l o i d s , sesquiterpenes, steroids and triterpenes. 20 In t h e i r t o t a l synthesis of ( +)- seychellene,Piers et a l used as the c r i t i c a l step the intramolecular c y c l i z a t i o n of keto tosylate (45) to give norseychellanone (46) which by stan-dard methods was converted into (+)-seychellene (47). O (45) (47) (46) - 2 3 -Nagata's group, i n t h e i r s y n t h e s i s of the d i t e r p e n e a l k a -l o i d a s t i s i n e , employed an i n t r a m o l e c u l a r c y c l i z a t i o n t o form 2 1 the proper C/D r i n g system ( 4 8 - M 3 ) In K e l l y ' s s y n t h e s i s o f (±)-ishwarane ( 5 1 ) the keto t o s y l a t e ( 4 9 ) upon base treatment underwent smooth c y c l i z a t i o n to form the r e q u i r e d t e t r a c y c l i c s k e l e t o n of ishwarane. T h i s ketone ( 5 0 ) was con v e r t e d i n t o (±)-ishwarane ( 5 1 ) by the Barton m o d i f i c a -TsO s y n t h e s i s of (±)-longifolene ( 5 4 ) , used as the c r i t i c a l step -24-the r e q u i r e d t r i c y c l i c keto a l c o h o l (53). The l a t t e r compound was subsequently transformed i n t o ( + ) - l o n g i f o l e n e (54). In the p a s t two decades numerous r e s e a r c h e r s have used t h i s type of r e a c t i o n s u c c e s s f u l l y and have thus t e s t i f i e d t o i t s syn-t h e t i c u t i l i t y . (B) ex" ;(? -UNSATURATED ALDEHYDES AND KETONES The i n t r a m o l e c u l a r a l k y l a t i o n of a $-unsaturated c a r b o n y l compounds has a l s o been used as the key r e a c t i o n i n the c o n s t r u c t i o n of p o l y c y c l i c compounds. S e v e r a l examples of i n t r a m o l e c u l a r a l k y l a t i o n s o f a ^ B - u n s a t u r a t e d ketones have been r e p o r t e d and some are d i s c u s s e d below. Thus Buchi's s y n t h e s i s of m a a l i o l i n v o l v e d c y c l i z a t i o n o f a, B -unsaturated keto bromide (55) by treatment o f the l a t t e r with methanolic potassium hy-24 d r o x i d e t o form the t r i c y c l i c carbon s k e l e t o n of m a a l i o l (56) 25 In t h e i r s y n t h e s i s o f (•£)-aromadendrene (59) , Buchi e t a l -25-used s i m i l a r condit ions and c y c l i z e d bromide (57) to the (55) (56) b i c y c l i c a g-unsaturated aldehyde (58). The l a t t e r compound was subsequently converted into (4)-aromadendrene (59). In the above examples, only gamma a l k y l a t i o n was r e a l i z e d , forming a cyc lopropy l d e r i v a t i v e . Another example of gamma a l k y l a t i o n of an a, g-unsaturated ketone,' as the exc lus ive product , i s shown below. Thus, treatment of cij8-unsaturated keto tosy la te (60) with potassium t-butoxide i n t - b u t y l a l coho l at 4 0 ° for 1.5 hours y i e lded the cyc lopropyl compound (61). Examples of gamma a l k y l a t i o n of an o^g-unsaturated ketone where a l l three modes of c y c l i z a t i o n were t h e o r e t i c a l l y possible 27 can also be found i n the l i t e r a t u r e . Thus, Bonet et a l con-verted the a,3 -unsaturated keto mesylate (62) into the y-alky-lated a (3~unsaturated ketone (63) by the action of sodium methoxide i n methyl alcohol. In Halperns' synthesis of a,3-unsaturated ketone (63), the keto tosylate (64) upon base -27-treatment underwent c y c l i z a t i o n which indicated that changing the leaving group from a mesylate to a tosylate had no a f f e c t on the p o s i t i o n of c y c l i z a t i o n . One further example where gamma 39 a l k y l a t i o n was the major process i s shown below . Thus, treatment of the a ,3-unsaturated keto tosylate (65) with potassium t-butoxide i n t-butyl alcohol yielded the gamma alkylated c t ;g -un-saturated ketone (66) . (65) (66) Examples of intramolecular a l k y l a t i o n reactions where a l l three modes of c y c l i z a t i o n were t h e o r e t i c a l l y possible but where i -28-the major product was the product of a - a l k y l a t i o n have also 29 been reported. Thus, treatment of the a,B -unsaturated keto mesylate (67) with sodium hydride i n dimethoxyethane containing some ethanol yielded the t r i c y c l i c B ;Y -unsaturated ketone (68) 30 i n 60% y i e l d as the major product. Turner et a l i n t h e i r approach to a diterpene a l k a l o i d synthesis c y c l i z e d the a (B -un-saturated keto epoxide (69) to the a alkylated B^Y-unsaturated keto alcohol (70) by treatment of the former with potassium t-butoxide i n t-butyl alcohol-benzene for one hour at 60°. (69) : (70) -29-F i n a l l y , the work of C a r g i l l et a l i l l u s t r a t e d the f e a s i b i l i t y of • a"-alkylation i n a variety of c^B -unsaturated ketones where a and y alkylations were also t h e o r e t i c a l l y possible. Thus treatment of the a,3-unsaturated keto bromides Br (73) (71), (72) and (73) with potassium t-butoxide i n t-butyl -30-a l c o h o l y i e l d e d the c orresponding products of a " a l k y l a t i o n . The examples of i n t r a m o l e c u l a r a l k y l a t i o n s of a ; B - u n s a t u r a t e d c a r b o n y l compounds t h a t have been d i s c u s s e d i n t h i s s e c t i o n have i l l u s t r a t e d c l e a r l y t h a t the products from a l l t h r e e t h e o r e t i c a l modes of c y c l i z a t i o n are found. In some cases, the s t r u c t u r a l f e a t u r e s were such t h a t o n l y y a l k y l a t i o n was r e a l i z e d . In o ther cases, where s e v e r a l s i t e s of a l k y l a t i o n seemed.possible, s e l e c t i v e l y f o r a l k y l a t i o n a t the alpha p o s i t i o n , gamma p o s i -t i o n or alpha prime p o s i t i o n where observed. •III. THE PROBLEM The l i t e r a t u r e i s s p o t t e d w i t h examples of i n t r a m o l e c u -l a r a l k y l a t i o n r e a c t i o n s of . a ( 3-unsaturated ketones. Products of every t h e o r e t i c a l l y p o s s i b l e mode of r e a c t i o n have been r e a l i z e d . But, as of y e t no d e f i n i t i v e study has been done to determine i f the s i t e of i n t r a m o l e c u l a r a l k y l a t i o n can be c o n t r o l l e d by v a r y i n g the r e a c t i o n c o n d i t i o n s . I t was our i n -t e n t i o n to c a r r y out such a study and to determine, i f p o s s i b l e , which parameters c o n t r o l l e d the s i t e of a l k y l a t i o n . More s p e c i f i c a l l y i t was our i n t e n t i o n t o s y n t h e s i z e the a ;ft -unsatur-q ated ketones (77a X=C1, 77b X=I) and (95 X=OSCH ), and t o 0 J vary the r e a c t i o n parameters such as base, s o l v e n t and l e a v i n g group (X) i n an e f f o r t to observe any change i n p o s i t i o n o f a l k y l a t i o n . ,X (77a) X=C1 (77b) X=I. (95) X=0S-CH3 -31-DISCUSSION I. PREPARATION OF 4 a-(3-CHLOROPROPYL)-4,4a,5,6,7,8— HEXAHYDRO-2-( 3H) -NAP HT HALE NONE (77a) and 4a- ( 3-IODOPROPYL)—  4, 4a, 5,6 , 7, 8-HEXAHYDRO-2-( 3H)-NAPHTHALENONE (77b) : The requisite a, 3-unsaturated keto chloride and iodide (77a,b) were readily prepared from cyclohexanone via an eight step sequence as outlined, in Scheme II. Conversion of cyclo-(77a) X=C1 (77b) X=I hexanone into the corresponding pyrrolidine enamine (79) was 32 accomplished according to the procedure of G. Stork . Treat-ment of the crude pyrrolidine enamine (79) with allyl bromide in refluxing acetonitrile, followed by hydrolysis of the resultant product with aqueous methyl alcohol yielded 2-allylcyclohexanone (80) in 60% yield. The conversion is shown below. Compound (80) was allowed to react with methyl vinyl ketone according to the 33 procedure of Marshall . Thus treatment of 2-allylcyclohexanone with methyl vinyl ketone in the presence of a catalytic amount of 3N sodium methoxide, under an atmosphere of nitrogen, and maintaining the reaction temperature at -10° C for 24 hours, -32--33-afforded a'mixture of two products, the g-hydroxy ketone (81) and the desired a;8 -unsaturated ketone (82). The ketol (81) was converted into the desired a ; B -unsaturated ketone (82) by treatment with sodium methoxide i n reflux i n g methyl alcohol for 2 hours. The octalone (82) was allowed to react with ethylene •OH (80) (82) (81) g l y c o l i n r e f l u x i n g benzene containing a c a t a l y t i c amount of p-toluenesulfonic acid to afford the ethylene ketal (83). The spectral data obtained from the l a t t e r compound was in complete 0 (82) (83) accord w i t h the a s s i g n e d s t r u c t u r e . Thus, the i n f r a r e d spec-trum showed no a b s o r p t i o n due to a c a r b o n y l f u n c t i o n a l i t y , an o b s e r v a t i o n which was i n l i n e with k e t a l f o r m a t i o n . The proton magnetic resonance (^"H N.M.R.) spectrum i n d i c a t e d the presence of f o u r o l e f i n i c protons and the presence o f f o u r e q u i v a l e n t methylene p r o t o n s , a t . 6-3.7, which c o u l d be r e a d i l y a t t r i b u t e d to the f o u r protons of the k e t a l f u n c t i o n a l i t y . Although the H H Z.H 0 0 s p e c t r a l data c o u l d not d i a g n o s t i c a l l y prove t h a t the double -35-bond had i n fact migrated during k e t a l i z a t i o n ; the structure i s written as-such since i t i s well known that during the formation of an ethylene k e t a l of an a ;B-unsaturated ketone, having gamma protons, the double bond w i l l isomerize out of conjugation . Spectral data derived from subsequent synthetic intermediates (see below) confirmed t h i s assignment. 40 Ethylene k e t a l (83) was subjected to hydroboratxon , using a dimethylsulfide-borane complex as the borane source. The reaction was done i n THF at room temperature for a period of - 3 6 -2 hours. At t h i s time the i n t e r m e d i a t e a l k y l b o r a n e was de-composed by treatment with a l k a l i n e hydrogen peroxide to afford the k e t a l a l c o h o l (84). The i n f r a r e d spectrum o f the l a t t e r com-pound showed the presence o f an a l c o h o l a b s o r p t i o n a t 34 50 cm"\ The N.M.R. spectrum was p a r t i c u l a r l y i n f o r m a t i v e , e x h i b i t i n g a broad m u l t i p l e t (IH) centered a t 6=5.4 r e a d i l y a t t r i b u t e d to the v i n y l p r o t o n . T h i s l a s t r e s u l t confirmed t h a t the double bond had i s o m e r i z e d d u r i n g k e t a l i z a t i o n . I f the double bond had remained conjugated to the k e t a l moiety then the v i n y l p r oton a b s o r p t i o n would have appeared as a s i n g l e t and not a m u l t i p l e t which i s t y p i c a l of a v i n y l p roton adjacent to other p r o t o n s . Other f e a t u r e s i n the ^ "H N.M.R. spectrum i n c l u d e d a s i n g l e t a t (£=4.0,due to the f o u r e t h y l e n e k e t a l protons. A l s o p r e s e n t was a m u l t i p l e t (2H) Centered a t 6=3.6 a t t r i b u t e d to the protons on the carbon atom b e a r i n g the hyd r o x y l group. , OH OMs (84) (85) The k e t a l a l c o h o l (84) was q u a n t i t a t i v e l y converted i n t o the c r y s t a l l i n e k e t a l mesylate (85) by treatment of the former w i t h methanesulfonyl c h l o r i d e and t r i e t h y l a m i n e i n methylene -37-chloride at 0°C for f o r t y - f i v e minutes. The 1H N.M.R. spec-trum of the ethylene ketal mesylate (85) showed a broad multi-p l e t centered at 6=5.5 due to the v i n y l proton. A multiplet centered at 6=4.3 could be attributed to the two protons on the carbon bearing the mesylate group. Additional features of the spectrum were the signals due to the mesylate methyl protons at 6=3.0, and the ethylene k e t a l protons at 6=3.8. OMs (85) GI (86) Treatment of the mesylate k e t a l (85) with 5 equivalents of lith i u m chloride i n reflux i n g acetone overnight afforded i n 94% y i e l d , a f t e r workup, the ethylene k e t a l chloride (86) . The "*"H N.M.R. spectrum showed a broad multi p l e t centered at 6 =5.48 due to the v i n y l proton. A s i n g l e t at 6 =3.9 8 attributed to the four ethylene ketal protons, and a multiplet centered at 6 =3.5 assigned to the two protons on the carbon bearing the chlorine atom. The above data, combined with the absence of a s i n g l e t due to the mesylate methyl protons were i n accord with the pro-posed structure for the ethylene k e t a l chloride (86). -38-A c i d h y d r o l y s i s of the e t h y l e n e k e t a l c h l o r i d e (86) u s i n g aqueous s u l f u r i c a c i d i n r e f l u x i n g acetone a f f o r d e d the ct;8 -un-s a t u r a t e d ketone c h l o r i d e (77a), as a y e l l o w o i l i n 90% y i e l d from the a l c o h o l . The i n f r a r e d spectrum of (77a) showed the presence of an a - u n s a t u r a t e d ketone c a r b o n y l a b s o r p t i o n a t 1660 cm"^. T h i s was i n a c c o r d w i t h the l o s s of the e t h y l e n e k e t a l f u n c t i o n a l i t y . The "*"H N.M.R. spectrum showed a s i n g l e t a t 6=5.75 due t o the v i n y l p r o t o n . The v i n y l p r o t o n a b s o r p t i o n was now s h i f t e d to lower f i e l d compared to the v i n y l proton ab--39-sorption of the ethylene ketal chloride (86). The s h i f t to lower f i e l d i s due to the deshielding e f f e c t of the carbon-carbon double bond and the carbonyl moiety. These results confirmed, that, as expected, the carbon-carbon double bond had isomerized back into conjugation with the carbonyl group. Had the double bond remained out of conjugation the mul-t i p l i c i t y of the signal due to the v i n y l proton would not be a si n g l e t but rather a multiplet since i t would remain adjacent to other protons. Treatment of the ethylene ketal mesylate (85) with f i v e equivalents of sodium iodide i n refl u x i n g acetone afford the ethylene k e t a l iodide (87). The 1H N.M.R. spectrum showed a broad multiplet centered at 6=5.4 due to the v i n y l proton, a si n g l e t centered at 6=3.9 attributed to the four ethylene k e t a l protons, and a multiplet centered at 6=3.2 assigned to the two protons on the carbon bearing the iodine atom. The above data combined with the absence of a si n g l e t due to the mesylate methyl protons, confirmed t h a t the proposed s t r u c t u r e f o r the ethyl e n e k e t a l i o d i d e was as w r i t t e n f o r compound (87). A c i d h y d r o l y s i s of the ethylene k e t a l i o d i d e (87) u s i n g aqueous s u l f u r i c a c i d i n r e f l u x i n g acetone a f f o r d e d , a f t e r the usu a l workup, the a,g-unsaturated ketone i o d i d e (77b) as a white c r y s t a l l i n e compound (m.p. 60-61°c)in 30% y i e l d from the a l c o h o l The "*"H N.M.R. spectrum of t h i s compound showed a s i n g l e t a t (87) (77b) ,6=5.7 due to the v i n y l p r o t o n , and a m u l t i p l e t c e n t e r e d a t <^5-=3.2 a t t r i b u t e d t o the two protons on the carbon b e a r i n g the i o d i n e atom. The i n f r a r e d spectrum showed the presence o f an ot^  8 - u n s a t u r a t e d c a r b o n y l a b s o r p t i o n a t 1655 cm~^. The i n f r a r e d spectrum and ^"H N.M.R. spectrum were i n ac c o r d w i t h the p r o -posed s t r u c t u r e f o r the ot,g-unsaturated ketone i o d i d e (77b) . The data confirms t h a t , as expected, the carbon-carbon double had i s o m e r i z e d back i n t o c o n j u g a t i o n w i t h the c a r b o n y l group. -41-II . INTRAMOLECULAR ALKYLATION STUDY (A) GENERAL CONSIDERATIONS: The octalone (77a) was subjected to a variety of a l k y l a t i o n reaction conditions i n an e f f o r t to determine what parameters, i f any, controlled the po s i t i o n of c y c l i z a t i o n . These r e s u l t s are summarized i n Table I. The general procedure used i n t h i s study was as follows. To begin with, a l l reactions were ca r r i e d out using 1.0 mmol of octalone (77a). Two equivalents (2.0 mmol ) of base were prepared under an atmosphere of nitrogen i n a three neck flask which had been previously flame dried, by adding 2.0 mmol of potassium metal to t-butyl alcohol. When the base used was potassium t-butoxide and any solvent other than t-butyl alcohol was employed the t-butyl alcohol was d i s t i l l e d and residual solvent removed under reduced pressure to afford potassium t-butoxide as a white powder. The appropriate solvent was then added to the anhydrous potassium t-butoxide. A solution of the octalone (77a) (1.0 mmol ) i n the required Cl 0 (77a) -42-solvent was subsequently added dropwise at room temperature and the reaction mixture was l e f t to s t i r at the appropriate temp-erature for the required length of time. I f the reaction solvent was t-butyl alcohol, the i n i t i a l l y employed t-butyl alcohol was not removed and the usual reaction procedure was followed. The volume of solvent used was the same for each run (40 ml). When lithium t-butoxide was the base used, i t was formed by adding two equivalents (2.0 mmol )of n-butyl lithium to 20 ml of t-butyl alcohol. This was followed by dropwise addition of octalone (77a) i n 20 ml of t-butyl alcohol. I f lithium diisopropylamide was the base, i t was prepared by treating a 1:1 mixture of diisopropylamine (2.0 mmol ): HMPA* (2.0 mmol ) solution (THF), with 2 equivalents of methyl lithium (2.0 mmol-). Aft e r the required length of time for the reaction to be complete, the reaction mixtures were quenched by pouring them into 0.1 N hydrochloric acid and the resultant mixture was extracted with ether.** The ether extracts were combined and washed with water and brine u n t i l neutral, dried over magnesium sulfa t e and evaporated to y i e l d a crude o i l . An ether solution of t h i s crude o i l was injected into a gas chromatograph to determine the product r a t i o s . At t h i s time one equivalent (1.0 mmol ) of a standard compound, previously shown to have an equal thermal conductivity * HMPA - hexamethylphosphoramide **When HMPA was solvent, Pet. ether was employed for extraction. -43-molar response, at the temperature of analysis, was added to the crude reaction mixture. A solution of the mixture was then injected into a gas chromatograph to determine the G.L.C. y i e l d . In simpler terms the l a s t sentence can be expressed i n the following way. I f one millimole of a certain compound i s combined with one millimole of another compound that has a thermal conductivity i d e n t i c a l to the f i r s t and t h i s mixture i s dissolved i n a solvent and injected into a gas chromatograph, then the respective peaks should be of equal area. This r e s u l t i s , of course, dependent on the fact that both compounds have the same thermal conductivity molar response for the gas chromatograph detector at the temperature that the chromatogram was taken. To determine a G.L.C. y i e l d , one simply expresses the area of the product peak as a percentage of the area of the standard peak. That i s to say, i f the reaction i s quanti-t a t i v e one would expect that both peaks should be of equal area and hence, expressed as a percentage the y i e l d would be 100%. The entire analysis mixture was then d i s t i l l e d under re-duced pressure and weighed. The i s o l a t e d y i e l d was then de-termined by subtracting the weight of the standard compound added from the t o t a l d i s t i l l e d weight to give the r e a l weight of product formed. I m p l i c i t i n t h i s analysis procedure was the assumption that a l l of the standard compound was d i s t i l l e d . This i s not a poor assumption since the temperature at which the standard compound d i s t i l l e d was s l i g h t l y lower than the temperature at which the product d i s t i l l e d . A l l the reactions were done in duplicate and the numbers in the tables represent an average value for the r a t i o s . The l i s t e d values showed a v a r i a t i o n of«^^% from the i n d i v i d u a l experimental values. When the reaction products were exposed to the same reaction and workup conditions as octalone (77a) they were recovered unchanged. This l a t t e r work insured that the product r a t i o s obtained were r e a l representations of i n t r a -molecular a l k y l a t i o n s and not the r e s u l t of a rearrangement of one or more of the products. • (B) INTRAMOLECULAR ALKYLATIONS INVOLVING 4a-(3-CHL0R0- PROPYL) -4, 4a, 5, 6 ,7, 8-HEXAHYDRO-2-( 3H) -NAPHTHALENONE (77a) 1. General Under the normal conditions f o r generating the therm-odynamic enolate anion (88), using potassium-t-butoxide i n t-butyl alcohol, one would expect c y c l i z a t i o n to occur at the a or Y positions and not at the a p p o s i t i o n , provided of course that a l k y l a t i o n of the i n i t i a l l y formed dienolate anion (89) i s much slower than e q u i l i b r a t i o n (rate-1^ rate3). Before undertaking t h i s study we considered the following parameters to be p o t e n t i a l l y i n f l u e n t i a l i n determining the p o s i t i o n of c y c l i z a t i o n . These factors were solvent, base, cation, temperature and cation complexing agents.' On the other hand, we f e l t that the e f f e c t of reactant concentrations would have minimal influence on the product r a t i o s . The r e s u l t s i n Table I c l e a r l y demonstrate that the above preliminary ex-pectations were i n fact f u l f i l l e d . -45-SCHEME I I I -46-2. E f f e c t of Solv e n t The o c t a l o n e (77a) was s u b j e c t e d to r e a c t i o n c o n d i -t i o n s where the thermodynamic e n o l a t e (88) was generated. Thus treatment o f o c t a l o n e (77a) with potassium t - b u t o x i d e i n t — b u t y l a l c o h o l a t room temperature f o r fou r hours r e s u l t e d i n the for m a t i o n o f two products ( a / &; 88/12)* i n 78% i s o l a t e d y i e l d (entry I, Tab l e 1)• T h i s r e s u l t i s i n accor d w i t h scheme I I I . Scheme I I I i n d i c a t e s t h a t i n order f o r the e q u i l i b r i u m to s h i f t t o the r i g h t to form d i e n o l a t e anion (88), a pro t o n source i s necessar y . S i n c e t - b u t y l a l c o h o l i s a p r o t i c s o l v e n t , w h i l e THF i s an a p r o t i c s o l v e n t one would expect a thermodynamic e q u i l -i b r a t i o n t o occur i n t - b u t y l a l c o h o l and a minimal e q u i l i b r a t i o n s h i f t i n THF. Thus the r e a c t i o n i n THF should show a decrease i n the amount of a a l k y l a t e d product. When o c t a l o n e (77a) was t r e a t e d w i t h 2 e q u i v a l e n t s (2.0 mmol ) of potassium t - b u t o x i d e i n THF a t room temperature f o r f o u r hours, a l k y l a t e d m a t e r i a l was i s o l a t e d i n 70% y i e l d . The r a t i o o f a/ a"'had, as expected, decreased and, i n f a c t , almost r e v e r s e d from a r a t i o of 88/12 * r e p r e s e n t i n g the product r a t i o as a / a / i n d i c a t e s the f o l l o w i n g : The mole r a t i o of compound (90) to compound (91) i s r e p r e -sented by a y y / a (90) (91) -47-observed i n t-butyl alcohol to a r a t i o of 15/85 observed i n THF. The e f f e c t of an aprotic solvent such as THF was to i n -crease the l i f e time of dienolate anion (89) s u f f i c i e n t l y for i t to alkylate before i t e q u i l i b r a t e d . HMPA, an aprotic solvent, has been shown to solvate cations 35 such as potassium ion . This solvating a b i l i t y of HMPA should increase the r e a c t i v i t y of anions. Thus treatment of octalone (77a) with two equivalents (2.0 mmol ) of potassium t-butoxide i n HMPA for 15 minutes afforded a mixture of a ' and a-alkylated products i n the r a t i o of 81/19. This r e s u l t i s i n accord with Scheme III where e q u i l i b r a t i o n of the i n i t i a l l y formed dienolate anion (89) was f a s t e r than a l k y l a t i o n (rate_2^rate3) r e s u l t i n g i n a higher proportion of a alkylated product than (^alkylated product. When comparing t h i s l a t t e r r e s u l t with the r e s u l t obtained i n the other aprotic solvent studied, namely THF, i t i s clear that the o v e r a l l rate of a l -k y l a t i o n i s f a s t e r i n HMPA and that the rate of a l k y l a t i o n of the thermodynamic enolate anion (88) i s f a s t e r than the rate of a l k y l a t i o n of the k i n e t i c dienolate anion (89) i . e . rate4^rate3. This enhanced r e a c t i v i t y i s a r e f l e c t i o n of the complexing a b i l i t y for cations found when HMPA i s employed as solvent, and i s a general feature observed i n other types of 35 reactions done i n HMPA where ion pairs are involved. 3. E f f e c t of Base In the above section solvent was the variable and potassium t-butoxide was always the base employed. To ascer-t a i n the e f f e c t of base we also considered lithium t-butoxide -48-and lithiu m diisopropylamide. When lithium t-butoxide was employed as base i n t-butyl alcohol (entry 6, Table I) there was no discernable reaction at room temperature a f t e r a 24 hour period. When comparing t h i s r e s u l t to the re s u l t obtained with potassium t-butoxide i n t-butyl alcohol i t becomes clear that the lithium dienolate anion (89) i s much less reactive than the potassium dienolate anion (89). This no doubt i s a re-f l e c t i o n of bond character, the lithium-oxygen bond having more covalent character, thus " t i g h t e r " , than the potassium-oxygen bond which i s less covalent. However, reflux i n g for six hours i n t-butyl alcohol afforded a mixture of ot and ^ a l k y l a t e d products i n the r a t i o of 57/39 respectively. This r e s u l t i s i n accord with Scheme III where a l k y l a t i o n of the i n i t i a l l y formed dienolate anion (89) i s s l i g h t l y slower than e q u i l i b r a t i o n . As previously demonstrated, i t i s possible to generate the k i n e t i c dienolate anion (89) under conditions where i t s i n t e g r i t y i s maintained by using lithiu m dialkylamides as bases i n an aprotic solvent. Thus treatment of octalone (77a) with 2 equivalents (2.0 mmol.) of a 1:1 mixture of lithium diisopropylamide: HMPA complex i n THF at room temperature f o r 3 hours afforded exclusively, i n 55% i s o l a t e d y i e l d , the pro-duct of a a l k y l a t i o n (entry 7, Table I ) . This r e s u l t i s i n accord with Scheme III where a l k y l a t i o n i s much fa s t e r than proton transfer. -49-4. E f f e c t of Complexing Agent - 18-Crown-6 The observed e f f e c t of adding two e q u i v a l e n t s (2.0 mmol :) of 18-crown-6 to the r e a c t i o n medium was two f o l d . F i r s t l y , i t g r e a t l y enhanced the r e a c t i o n r a t e , d e c r e a s i n g the r e a c t i o n time necessary f o r disappearance of s t a r t i n g m a t e r i a l from f o u r hours t o f i f t e e n minutes. Secondly, the amount o f a a l k y l a t e d product was i n c r e a s e d from 88% to 95% of the t o t a l p r o d u c t i n t - b u t y l a l c o h o l (entry 2, Table I ) . The observed e f f e c t of 18-crown-6 was t o i n c r e a s e the r a t e of e q u i l i b r a -t i o n t o form the thermodynamic d i e n o l a t e anion (88)and to enhance the r a t e o f a l k y l a t i o n . 18-crown-6 e t h e r complexes w i t h the potassium c a t i o n and l e a v e s the d i e n o l a t e anion uncomplexed and thus more r e a c t i v e . I t i s not s u r p r i s i n g t h a t 18-crown-6 enhances the r a t e o f n u c l e o p h i l i c r e a c t i o n s s i n c e t h i s type o f 3 6 behaviour has l i t e r a t u r e precedent. When 18-crown-6 i s added to a THF s o l u t i o n c o n t a i n i n g potassium t - b u t o x i d e and o c t a l o n e (77a) the e f f e c t i s v i r t u a l l y the same as i n t - b u t y l a l c o h o l . Thus a d d i t i o n of 2 e q u i v a l e n t s o f 18-crown-6 (2.0 mmol ) to a THF s o l u t i o n of o c t a l o n e (77a) c o n t a i n i n g (2.0 mmol ) of potassium t-butoxide showed an enhance-ment of the r e a c t i o n r a t e c a u s i n g completion of r e a c t i o n i n 15 minutes r a t h e r than f o u r hours. The product r a t i o was a l s o a f f e c t e d showing an i n c r e a s e i n the amount of . a - a l k y l a t e d p r o -duct from an- a / ^ r a t i o of 15/85 to 35/62. 5. S y n t h e t i c A p p l i c a t i o n As p r e v i o u s l y d i s c u s s e d , (entry 3, T a b l e 1) when o c t a l o n e (77a) was t r e a t e d w i t h potassium-t-butoxide i n THF a t -50-room temperature the major product was the one from xx -alky-l a t i o n . This indicated that a l k y l a t i o n was fa s t e r than proton transfer i n t h i s solvent. I f the reaction was c a r r i e d out at a lower temperature one might expect a decrease i n the rate of a l k y l a t i o n . Also, by adding some t-butyl alcohol to t h i s THF solution, thereby introducing a good proton source, the rate of e q u i l i b r a t i o n (proton transfer) should increase even more. In addition, i f an equivalent of 18-crown-6 ether was added to th i s t-butyl alcohol - THF solution, e q u i l i b r a t i o n might be ex-pected to occur s t i l l f a s t e r . Thus, the above mentioned conditions were combined and 1.0 mmol of octalone (77a) was allowed to react with 2.0 mmol of potassium t-butoxide i n a mixture of t-butyl alcohol - THF (60/40) containing 2.0 mmol of 18-crown-6 at -78°. The reaction mixture was subsequently allowed to warm up to room temperature with s t i r r i n g f o r an addit i o n a l 15 minutes. Under these con-d i t i o n s none of the .a-alkylated product was obtained. The only i d e n t i f i a b l e product i s o l a t e d was the product due to a-alkylation accompanied by an un i d e n t i f i e d compound i n the r a t i o of 95:5. This r e s u l t combined with the r e s u l t obtained employing lithium diisopropylamide as base i n THF (entry 7, Table I) com-pliment each other s y n t h e t i c a l l y . That i s to say these r e s u l t s are s y n t h e t i c a l l y u s e f u l , i n that i t i s now possible to form e i t h e r the product of cx'alkylation or the product of .a - a l k y l a -t i o n . At no time was the product of y-alkylation detected (see below for proof). -Si-te) INTRAMOLECULAR ALKYLATIONS INVOLVING 4a-(3-IODO- PROPYL )-4,4a,5,6,7, 8-HEXAHYDRO- 2-( 3H) -NAPHTHALENONE (77b) The effect of changing the leaving group was also studied and the results are recorded in Table I. When the leaving group was changed from chloride to iodide quite different results were obtained. Since the rate of expulsion of a leaving group X, (where x is a halide ion), decreases in the series I~^Br~^Cl~^F~, we felt that, a priori, iodide would be a "better" leaving group. We had anticipated that the reactions would occur faster and that more a'-alkylated product would be formed. That is to say, alkylation of the initially formed dienolate anion (91a) would be faster than equilibration. (91) 0' r p + [11 (92) (90) SCHEME IV TABLE I - INTRAMOLECULAR ALKYLATION OF OCTALONE (77aft) -X ENTRY BASE ADDED REAGENT SOLVENT REACTION CONDITIONS YIELD G.L.C. ISOLATED RATIO OF PRODUCTS OTHER CI 1 KfcOBu t-BuOH 4 hr. R.T. 80 . 78 12 88 CI 2 KfcOBu 18-Crown-6 t-BuOH 15 min R.T. 72 71 5 95 CI 3 K^Bu THF 4 hr. R.T. 74 70 85 15 C l 4 K tOBu 18-Crown-6 THF 15 min R.T. 52 51.5 65 35 CI 5 KfcOBu HMPA 15 min R.T. 65 64 19 81 C l 6 Li f cOBu t-BuOH 6 hr. r e f l u x 81 77 39 57 C l 7 LDA,HMPA THF 3 hr. R.T. 56 55 100 0 C l 8 KfcOBu 18-Crown-6 t-BuOH/THF 40/60 30 15 min min -78° R.T. 62 61 0 95 I 9 KfcOBu t-BuOH 15 min R.T. 100 94 100 0 I 10 KfcOBu 18-Crown-6 t-BuOH 15 min R.T. 91.5 90 78 22 I 11 K tOBu t-BuOH/THF 40/60 30 15 min min -7 8° R.T. 67 65 74 20 - a l l e n t r i e s done i n d u p l i c a t e . Unless stated otherwise, 2 equivalents of base was employed. - products are stable to rea c t i o n c o n d i t i o n s . i I J -53-Thus treatment of the iodide derivative, octalone (77b), with potassium t-butoxide i n t-butyl alcohol at room tempera-ture for 15 minutes resulted i n the exclusive formation of the product from a - a l k y l a t i o n i n 94% i s o l a t e d y i e l d . This r e s u l t was i n accord with Scheme IV with proton-transfer being very slow compared to a l k y l a t i o n . This r e s u l t was not too sur-p r i s i n g , but did eliminate the necessity of undertaking experi-ments i n aprotic solvents such as THF. Since a l k y l a t i o n of the k i n e t i c dienolate anion (91a) was much fa s t e r than proton trans-fer even i n the presence of a large amount of p r o t i c solvent, (t-butyl a l c o h o l ) , i t was f e l t that changing to an aprotic solvent would not provide additional synthetic information as to the method of forming a - a l k y l a t e d product. What e f f e c t a complexing agent, such as 18-crown-6 would have on the product r a t i o a/ a"' ' was studied next. As pre-viously noted (above section), 18-crown-6 was observed to increase the rate of e q u i l i b r a t i o n . Therefore, the addition of 18-crown-6 to a s o l u t i o n of octalone (77b), might be ex-pected to a l t e r the r a t i o of -9 /a' from 100% a - a l k y l a t e d pro-duct to perhaps form some a-alkylated product. Thus treatment of octalone (77b) (1.0 mmol ) with 2 equivalents of potassium t-butoxide (2.0 mmol ) i n t-butyl alcohol containing 2 equiva-lents (2.0 mmol •) of 18-crown-6 at room temperature for 15 min-utes afforded, i n 90% i s o l a t e d y i e l d , a mixture of a and a' a l -kylated products i n a r a t i o of 22/78 (entry 10, Table I ) . As expected, 18-crown-6 increased the rate of proton transfer and thus decreased the amount of a-^alkylated product r e l a t i v e to the amount of '• a-alkylated product. -54-(D) SUMMARY OF INTRAMOLECULAR ALKYLATION STUDIES Synth e t i c a l l y , these r e s u l t s are very s i g n i f i c a n t . We have been able to form exclusively the product of a ^ -alkylation i n 94% is o l a t e d y i e l d under one set of reaction conditions, and the product of a - a l k y l a t i o n almost exclusively ()95%), i n good y i e l d , under another set of conditions. At no time was the product of y-alkylation detected. The foregoing r e s u l t s have shown that c e r t a i n factors are important i n determining the pos i t i o n of intramolecular a l k y l a -t i o n of a,$-unsaturated ketones. These factors include solvent, cation, complexing agent, base and leaving group. I t has been c l e a r l y demonstrated when the substrate i s octalone (77a), that i n a p r o t i c solvent, such as t-butyl alcohol, the major product was the product of a a l k y l a t i o n , whereas i n an aprotic solvent such as THF, the major product was the product of a^alkylation. When judging the e f f e c t of cation, two differences emerge. F i r s t l y , the potassium enolate i s much more reactive than the lithium enolate. Secondly, the lithium enolate forms less a-alkylated product i n t-butyl alcohol than the potassium enolate (compare entry 1 and 6, Table I ) . The e f f e c t of 18-crown-6 was to increase the rate of e q u i l i b r a t i o n as well as to increase the o v e r a l l rate of a l -k y l a t i o n . When 1 equivalent of 18-Orown-6 was added to the reaction mixture, whether i t was an aprotic solvent (THF) or a p r o t i c solvent (t-BuOH) the r e s u l t was an increase i n the amount o-f a -alkylated product. A d i r e c t comparison on how the leaving group a f f e c t s the -55-d i r e c t i o n of i n t r a m o l e c u l a r c y c l i z a t i o n can be seen when com-p a r i n g the r e s u l t s i n en t r y 1, T a b l e I t o en t r y 10, Tab l e I . One q u i c k l y n o t i c e s t h a t i o d i d e i s a much b e t t e r l e a v i n g group than c h l o r i d e (see equations 8 and 9) . (E) STRUCTURAL ASSIGNMENT OF ALKYLATION PRODUCTS The products of a - a l k y l a t i o n , compound (9 0) and a - a l k y -l a t i o n , compound (91), were o b t a i n e d as a mixture i n a r a t i o o f 88:12 r e s p e c t i v e l y when o c t a l o n e 77a was t r e a t e d w i t h potassium t - b u t o x i d e i n t - b u t y l a l c o h o l a t room temperature f o r 4 hours. The crude r e a c t i o n products were s u b j e c t e d to column chromotography, u s i n g s i l i c a g e l packing and e l u t i n g w i t h a petroleum e t h e r - e t h e r mixture, t o y i e l d pure o c t a l o n e (90) and pure o c t a l o n e (91) (see e x p e r i m e n t a l ) . -56-(91) (90) " (92) a'- PRODUCT a-PRODUCT y-PRODUCT The "^H N.M.R. spectrum of o c t a l o n e (90) e x h i b i t e d a t r i p l e t c e n t e r e d at 6 =5.55 (J=36hz) fwhich c o u l d r e a d i l y be a t t r i b u t e d t o the v i n y l p r o t o n . The i n f r a r e d spectrum c o n t a i n e d a s a t -u r a t e d c a r b o n y l a b s o r p t i o n a t 1710 cm ^. The above data i s i n a c c o r d w i t h the proposed s t r u c t u r e f o r o c t a l o n e (90). The N.M.R. spectrum of the a - a l k y l a t e d product, o c t a l o n e (91), showed a s i n g l e t a t 6=6.02 which c o u l d r e a d i l y be ass i g n e d t o the v i n y l p r o t o n alpha to the c a r b o n y l group. The i n f r a r e d spectrum showed the presence o f an a 3 -unsaturated c a r b o n y l a b s o r p t i o n a t 167 0 cm \ The above data i s i n accord w i t h the proposed s t r u c t u r e f o r o c t a l o n e (91) as w e l l as f o r o c t a l o n e (92), the prod u c t o f y a l k y l a t i o n . The s t r u c t u r e o f the pro-duct of a - a l k y l a t i o n , an a ^-unsaturated ketone (91) c o u l d be d i s t i n g u i s h e d from the product of y - a l k y l a t i o n , an a B -un-s a t u r a t e d ketone (92) by the f o l l o w i n g chemical sequence. -57-(90) (92) Thus, treatment of octalone (90) under modified Wolff-37 Kishner reduction conditions , to e f f e c t reduction of the carbonyl group, using sodium glycolate and anhydrous hydra-zine, afforded the alkene hydrocarbon (93) i n 81% i s o l a t e d y i e l d . The "^H N.M.R. spectrum showed a well resolved t r i p l e t centered at 6 = 5.4 which could rea d i l y be attributed to the v i n y l proton. The i n f r a r e d spectrum contained no carbonyl absorption which was in accord with the structure assigned to compound (93). Hydrocarbon (93) was then treated with a chromium t r i -3 8 oxide-pyridine complex (Collins reagent) i n methylene chloride for 6 hours to e f f e c t a l l y l i c oxidation and form i n 85% i s o l a t e d y i e l d , the product of ^ - a l k y l a t i o n , compound (92). The *H N.M.R. spectrum of compound (92) was very informative exh i b i t i n g a s i n g l e t at 6=5.76 which could r e a d i l y be a t t r i -buted to the v i n y l proton adjacent to the carbonyl group. The i n f r a r e d spectrum of compound (92) showed the presence of an 1 6 7 0 cm -1 H § = 6 . 0 2 (91 ) 1 6 6 0 cm -1 H 6=5.76 (92) rxt3 -unsaturated ketone carbonyl absorption at 1660 cm x . Direct comparison of the spectral data obtained from compound (92) with the spe c t r a l data exhibited by compound (91) diag-n o s t i c a l l y proved that the a,3 -unsaturated ketone obtained, i n the above intramolecular a l k y l a t i o n study, was i n fact the pro-duct of a - a l k y l a t i o n and not the product of y-alkylation. I I I . PREPARATION OF 4a-(MESYLATE METHYL)-4,4a,5,6,7,8-HEXA- HYDRQ- 2-( 3H) -NAPHTHALFNONE (95) The re s u l t s obtained from the above study, (section B and C), c l e a r l y indicated that the p o s i t i o n at which intramolecular a l k y l a t i o n of compounds (77a) and (77b) had occurred was de-pendent on a number of parameters. One further variable we wished to explore was the e f f e c t of ring s i z e . By varying the s ide chain length as i n compound (96),the s ize of the r ing formed would be e f f e c t i v e l y a l t e r e d . The f i r s t stage of t h i s study required the synthesis of compound (95). The r e q u i s i t e a ,B-unsaturated keto mesylate (95) was r e a d i l y prepared from 4a-(carbomethoxy)-4,4a,5,6,7,8-hexahydro 2-(3H)-naphthalenone (97) as ou t l ined i n the scheme below. The l a t t e r compound was allowed to react with ethylene g l y c o l i n benzene containing a c a t a l y t i c amount of p- to luenesul fonic -60-COOCH. COOCH. (97.) .OMs pTsOH MsCl E t 3 N CH 2C1 2 " 0 H 2 S 0 4 / H 2 ° Acetone DMs (•95) a c i d . The mixture was r e f l u x e d , u s i n g a Dean-Stark apparatus, o v e r n i g h t to y i e l d the eth y l e n e k e t a l e s t e r (98). The s p e c t r a l data obtained from the l a t t e r compound was i n complete acc o r d w i t h the as s i g n e d s t r u c t u r e . Thus, the - i n f r a r e d spectrum showed no a b s o r p t i o n due to an e^g-unsaturated c a r b o n y l func-t i o n a l i t y , an o b s e r v a t i o n which was i n l i n e w i t h k e t a l formation. The "^H N.M.R. spectrum i n d i c a t e d the presence o f a broad mul--61-t i p l e t , c e n tered at 6 = 5.7 a t t r i b u t e d to the v i n y l p roton i n compound (98). Other f e a t u r e s of the N.M.R. spectrum were s i n g l e t s a t 6 = 4.0 and.6 = 3.7. The l a t t e r s i g n a l c o u l d be r e a d i l y a t t r i b u t e d to the three protons o f the methyl e s t e r group and the former to the fo u r e q u i v a l e n t e t h y l e n e k e t a l p r o-tons . The e t h y l e n e k e t a l e s t e r (98) was s u b j e c t e d t o r e d u c t i o n c o n d i t i o n s , u s i n g l i t h i u m aluminum h y d r i d e i n THF a t room temperature f o r 1 hour. A f t e r the u s u a l workup procedure, the k e t a l a l c o h o l (99) was o b t a i n e d as a white c r y s t a l l i n e compound m.p. 89-91°C.4''" The i n f r a r e d spectrum showed a t y p i c a l h y d r o x y l a b s o r p t i o n a t 3500 cm ^. The l o s s of the e s t e r c a r b o n y l group was confirmed by the l a c k o f an a b s o r p t i o n a t 1720 cm~^. The "'"H N.M.R. spectrum showed a sharp s i n g l e t a t 5=3.25, which c o u l d be r e a d i l y a t t r i b u t e d to the two protons on the carbon b e a r i n g the h y d r o x y l group. A d d i t i o n a l f e a t u r e s of the spectrum were s i g n a l s at 6=5.1 and 6=3.6. The former a b s o r p t i o n was due to -62-(98) -(99) the v i n y l p r o t o n and the l a t t e r s i n g l e t c o u l d be r e a d i l y a t t r i b u t e d to the f o u r e t h y l e n e k e t a l p r o t o n s . The k e t a l a l c o h o l (99) was converted i n t o the c r y s t a l l i n e k e t a l mesylate (100) (m.p. 102-102.5°C) by treatment of the former w i t h methanesulfony1 c h l o r i d e and t r i e t h y l a m i n e i n methylene c h l o r i d e a t 0° f o r 1 hour. The "^H N.M.R. spectrum of the e t h y l e n e k e t a l mesylate (100) showed a broad m u l t i p l e t c e n t e r e d a t .6 = 5.6 due to the v i n y l p r o t o n . A m u l t i p l e t cen-t e r e d a t 4=4.2 c o u l d be a t t r i b u t e d t o the two protons on the carbon b e a r i n g the mesylate group. A d d i t i o n a l f e a t u r e s of the spectrum i n c l u d e d s i g n a l s due to the mesylate methyl protons at 6=3.0 and the et h y l e n e k e t a l protons a t 6=3.85. A c i d h y d r o l y s i s o f the et h y l e n e k e t a l mesylate (100) us i n g aqueous s u l f u r i c a c i d i n r e f l u x i n g acetone o v e r n i g h t , a f f o r d e d the d e s i r e d a ^ - u n s a t u r a t e d ketone mesylate (95) as a white c r y s t a l l i n e compound m.p. 98-99°C. The i n f r a r e d spectrum of compound (95) showed the presence of an a,£-un-s a t u r a t e d ketone c a r b o n y l a b s o r p t i o n at 1670 cm T h i s obser v a t i o n was i n a c c o r d w i t h the l o s s of the e t h y l e n e k e t a l func-t i o n a l i t y . The N.M.R. spectrum showed a s i n g l e t at6=3.0 due t o the t h r e e methyl protons of the mesylate group. A s i n g l e t a t .6=4.33 c o u l d be r e a d i l y a t t r i b u t e d to the two pr o -tons on the carbon b e a r i n g the mesylate group. L a s t l y , the "*"H N.M.R. showed the presence o f a broad s i n g l e t at;.6 = 5.8 due to the v i n y l p r o t o n a d j a c e n t to the c a r b o n y l group. -64-IV. INTRAMOLECULAR ALKYLATION STUDY INVOLVING 4a-(MESYLATE METHYL)- 4,48,5,6,7, 8-HEXAHYDRO-2-j3H) -NAPHTHALENONE (95) (A) GENERAL COMMENTS Octalone (95) was subjected to a variety of a l k y l a t i o n conditions i n an attempt to determine what parameters controlled the p o s ition of a l k y l a t i o n . These results are summarized i n Table I I . The general procedure used i n thi s study was as follows. F i r s t of a l l , the reactions were carr i e d out using 195)' 1.0 mmol of octalone (95). Two equivalents (2.0 mmol ) of base were prepared by adding (2.0 mmol' ) of potassium metal to t-butyl alcohol. This procedure was carr i e d out under an atmosphere of nitrogen i n a three neck flask which had been previously flame dried. When the base used was potassium t — butoxide and any solvent other than t-butyl alcohol was em-ployed, the t-butyl alcohol was d i s t i l l e d and the re s i d u a l solvent removed under reduced pressure to afford potassium t — butoxide as a white powder. The appropriate solvent was then added to the anhydrous potassium t-butoxide. -65-A solution of the octalone (95) (1.0 mmol ) in the required solvent was subsequently added dropwise at room temperature and the reaction mixture was l e f t t o - s t i r at the appropriate temp-erature for the required length of time. When the reaction medium was t-butyl alcohol, the i n i t i a l l y employed t-butyl alcohol was not removed and the usual reaction procedure was followed. The t o t a l volume of solvent used was the same (40 ml ) for each run. When lithium t-butoxide was the base used, i t was formed by adding two equivalent's (2.0 mmol ) of n-butyl lithium to 20 ml of t-butyl alcohol. This was followed by the dropwise addition of octalone (95) i n 20 ml. of t-butyl alcohol. Lithium diisopropylamide was prepared i n THF from 2.0 mmol of diisopropylamine and 2 mmo3 of methyl lithium. After the required length of time for the reaction to be complete, the reaction mixtures were quenched by pouring them into 0.1 N hydrochloric acid and the resultant mixture was * extracted with ether. The ether extracts were combined and washed with water and brine u n t i l neutral, dried (MgSO^), and evaporated to y i e l d a crude o i l . An ether solution of thi s crude o i l was then injected into a gas chromatograph to determine the product r a t i o s . At this time, one equivalent (1.0 mmol ) of a "standard compound", was added to the crude reaction mixture and a solu-t i o n of the r e s u l t i n g mixture was injected into a gas chroma-*When HMPA was solvent, a Pet. Ether-Ether (3:1) mixture was employed for extraction. -66-tograph t o determine the G.L.C. y i e l d . * The e n t i r e a n a l y s i s mixture was then d i s t i l l e d under reduced p r e s s u r e and weighed. The i s o l a t e d y i e l d was then determined by s u b t r a c t i n g the weight of the standard compound from the t o t a l d i s t i l l e d weight to g i v e the a c t u a l weight of product formed. A l l the r e a c t i o n s were run i n d u p l i c a t e and the numbers i n Table II r e p r e s e n t an average value f o r the r a t i o s . The l i s t e d v a l u e s showed a v a r i a t i o n o f ±%% from the i n d i v i d u a l e x p e r i m e n t a l v a l u e s . *For a f u l l account see s e c t i o n II p a r t (A). (B) INTRAMOLECULAR ALKYLATION OF MESYLATE (95) 1. General Under the normal c o n d i t i o n s f o r g e n e r a t i n g the thermo-d y n a m i c a l l y favoured e n o l a t e (101) us i n g potassium t-butoxide i n t - b u t y l a l c o h o l , one would expect c y c l i z a t i o n to occur at the a or y p o s i t i o n and not a t the a p p o s i t i o n . The above statement i s t r u e p r o v i d e d t h a t a l k y l a t i o n of the i n i t i a l l y formed d i e n o l a t e anion (102) i s much slower than proton t r a n s f e r ( r a t e _ i ^ rate3) . (103) (104) (66) J -68-Examples of systems containing an angular one carbon chain which have been subjected to intramolecular a l k y l a t i o n conditions can be found i n the l i t e r a t u r e . A few examples are l i s t e d below. Some i n t e r e s t i n g observations can be made from these examples. F i r s t l y , in a l l cases c i t e d a p r o t i c solvent was employed. Secondly, the base used was a metal alkoxide. (65) (66) T h i r d l y , the po s i t i o n of al k y l a t i o n was, i n a l l cases, gamma to the carbonyl group. These results are i n accord with Scheme IV where proton transfer of the i n i t i a l l y formed enolate anion i s much faster than a l k y l a t i o n . However, the factors responsible for exclusive gamma a l k y l a t i o n are as yet not clea r . Before undertaking t h i s study i t was f e l t that, as i n the previously described study (section I I ) , cert a i n parameters would be p o t e n t i a l l y i n f l u e n t i a l i n determining the po s i t i o n of a l k y l a t i o n . These factors were, solvent, base and complexin agent. On the other hand i t was f e l t that factors such as temperature,reaction concentration and cation would have l i t t l e or minimal influence on the product r a t i o . The r e s u l t s in Table II c l e a r l y indicate that the above preliminary expecta-tions, at least in part, were i n fact f u l f i l l e d . tions where the thermodynamic enolate anion (101) was generated Thus treatment of keto mesylate (95) with potassium t-butoxide i n t-butyl alcohol at room temperature for twenty hours re-sulted i n the formation of a single product i n 74% i s o l a t e d y i e l d as a colourless o i l . The product proved to be the one formed v i a y - a l k y l a t i o n (see experimental). This r e s u l t i s i n accord with Scheme IV where a l k y l a t i o n of the i n i t i a l l y formed dienolate anion (102) i s slower than proton transfer ( r a t e _ ] ^ r a t e 3 ) . 2. E f f e c t of Solvent The octalone (95) was subjected to reaction condi--70-OMs - 0 OMs P O (103) (95) Changing the r e a c t i o n medium from a p r o t i c s o l v e n t , such as t - b u t y l a l c o h o l , to an a p r o t i c s o l v e n t , such as THF, should decrease the r a t e of e q u i l i b r a t i o n r e l a t i v e to the r a t e of a l k y l a t i o n o f the i n i t i a l l y formed d i e n o l a t e anion (102). From Scheme IV i t i s c l e a r t h a t i n order f o r the e q u i l i b r i u m to s h i f t i n favour o f the thermodynamically more s t a b l e d i e n o l a t e anion (101), a proton source i s necessary. S i n c e t - b u t y l a l c o h o l i s a p r o t i c s o l v e n t , w h i l e THF i s an a p r o t i c s o l v e n t , one would expect an e q u i l i b r a t i o n to occur i n t - b u t y l a l c o h o l and a minimal e q u i l i b r i u m s h i f t i n THF. Thus, the r e a c t i o n i n THF should show an i n c r e a s e i n the amount of product formed i n THF compared to t - b u t y l a l c o h o l . Treatment of keto mesylate (95) (1.0 mmol ) w i t h (2.0 mmol ) of potassium t - b u t o x i d e i n THF a t room temperature f o r 20 hours a f f o r d e d , a f t e r the u s u a l workup, a s i n g l e compound as a c o l o u r -l e s s o i l i n 61% i s o l a t e d y i e l d . T h i s product proved t o be the product of Y - a l k y l a t i o n (see e x p e r i m e n t a l ) . -71-The t h i r d solvent studied was HMPA. HMPA i s a dipolar aprotic solvent which i s known to solvate cations such as potassium and thus renders the enolate anion more reactive. We f e l t that a reactive enolate anion would c y c l i z e at a posi-t i o n other than the gamma po s i t i o n . Thus treatment of keto mesylate (95) (1.0 mmol- ) with 2.0 mmol.. of potassium t — butoxide i n HMPA at room temperature for 1 hour afforded a product mixture which showed two components by G.L.C. i n a r a t i o of 20/80 for compounds ( y/a"). Coinjection of thi s mix-ture with authentic gamma alkylated product showed that the minor component had the same retention time as the gamma a l -kylated product. The infrared spectrum of the mixture showed a large absorption, 1730 cm ^, which could be readi l y a t t r i -buted to a saturated carbonyl. This r e s u l t strongly indicated that the major product was the product of a - a l k y l a t i o n . A comparison of the re s u l t s thus far discussed, (and i n the e n t i r e study of keto mesylate (95)), c l e a r l y indicated •representing the product r a t i o asfy/a) indicates the following The mole r a t i o of compound (66) to (66) compound (104) i s represented by (Y / C ) C104) -72-that d i f f e r e n t r e s u l t s were obtained when HMPA was employed as the solvent. I t would appear l o g i c a l at th i s time to examine and compare the possible t r a n s i t i o n states of the reaction i n the three solvents studied. In a p r o t i c solvent such as t-butyl alcohol, one would expect the enolate anion to be heavily solvated. This condition, would render the enolate anion less reactive r e l a t i v e to a less solvated enolate anion such as one formed i n THF or HMPA. From t h i s i t could be argued that the geometry of the t r a n s i t i o n state f o r a l k y l a t i o n would be more product-like than reactant-l i k e and the r e l a t i v e s t a b i l i t y of the a-alkylated product or the y-alkylated product would be r e f l e c t e d i n the r e l a t i v e energy of the two possible t r a n s i t i o n states (see Scheme V). That i s to say, i n t-b u t y l alcohol and in THF the t r a n s i t i o n state for y-alkylation i s of lower energy leading to the more stable af 3-unsaturated ketone (66) and not to the less stable (66) (104) 3^y-unsaturated ketone (104). However, i n HMPA, a solvent known for i t s a b i l i t y to solvate 34 cations , one would expect the enolate anion to be r e l a t i v e l y SCHEME V -74-"free" and therefore r e l a t i v e l y more reactive than i n THF or t-butyl alcohol. From th i s i t could be argued that the t r a n s i -tion state geometry leading to intramolecular a l k y l a t i o n should be more reactant-like and therefore the r e l a t i v e s t a b i l i t y of the product(s) should have minimal influence on the course of the reaction. 3. E f f e c t of Base To ascertain the e f f e c t of base, on the po s i t i o n of intramolecular a l k y l a t i o n of keto mesylate (95), we also con-sidered l i t h i u m t-butoxide and lithium diisopropylamide. When lithium t-butoxide was employed as base i n t-butyl alcohol there was no sign of any product formation at room temperature. However, when the l a t t e r s o l u t i o n was refluxed for 24 hours, the product of y - a l k y l a t i o n was i s o l a t e d exclusively. When com-paring t h i s r e s u l t to the r e s u l t obtained with potassium t — butoxide i n t-butyl alcohol i t becomes cle a r that the lit h i u m dienolate anion (101) i s much less reactive than the potassium dienolate anion (101). As mentioned i n the previous study t h i s r e a c t i v i t y difference between the potassium enolate (101) and the lithium enolate (101) i s probably a r e f l e c t i o n of the res-pective metal-oxygen bond character. The lithium-oxygen bond i s more covalent than the potassium-oxygen bond. As previously demonstrated, i t i s possible to generate the k i n e t i c dienolate anion (102) under conditions where i t s i n t e g r i t y i s maintained by employing lithium diisopropylamide as base i n an aprotic solvent such as THF. Under these condi-tions i t should be possible to form some a-slkylated product. TABLE I I - INTRAMOLECULAR ALKYLATION5 OF KETO MESYLATE (95) 0 OS-CH (95) ADDED REACTION YIELD X ENTRY BASE • REAGENT SOLVENT CONDITIONS GLC ISOLATED PRODUCT RATIO 0M5 1 K ^ B u t-BuOH 20 h r s . R.T. 77 74 0 100 OMs 2 K ^ B u 18-Crown-6 t-BuOH 45 min. R.T. 72.6 71 0 100 OMs 3 K ^ B u THF 20 h r s . R.T. 63 60.5 0 100 OMS 4 Li f cOBu t-BuOH 20 h r s . r e f l u x 79 74 0 100 OMs 5 LDA THF 2 days r e f l u x 96 92 0 100 OMs 6 KfcOBu HMPA 1 hr. R.T. 74. 3 73 80 20 OMs 7 KfcOBu 18-Crown-6 HMPA 30 min. R.T. 77.7 75 92 8 • A l l e n t r i e s done i n d u p l i c a t e . 2 e q u i v a l e n t s o f base used i n a l l cases. I U l I -76-1102). (103) Treatment of octalone (95) (1.0 mmol ) with (2.0 mmol ) of l i t h i u m diisopropylamide i n THF for 2 4 hours at room tempera-ture afforded only the s t a r t i n g material. However, when the above solution was refluxed for 2 days, the product of gamma al k y l a t i o n was formed exclusively. The above experimental r e s u l t s , were, to say the l e a s t , very unexpected. That the i n i t i a l expectations were not f u l -f i l l e d can only lead to the conclusion that a l k y l a t i o n of the k i n e t i c dienolate anion (102) i s a very unfavourable process. An examination of models of the two possible dienolate anions (102), (101) leading to the three possible products (103), (104) and (66), does not provide any information as to the reason for not observing any a "-alkylated product. From an examination of the models, a l l three products seem l i k e l y to be formed. Therefore, f o r reason(s) unknown to us, the k i n e t i c dienolate anion (102), at l e a s t i n our hands under the reaction -77-conditions employed, did not alkyla t e , just e q u i l i b r a t e d . 4. E f f e c t of Complexing Agent The observed e f f e c t of adding (2.0 mmol ) of 18-crown— 6 to the reaction medium was that i t greatly enhanced the reac-tion rate, decreasing the reaction time necessary for the d i s -appearance of s t a r t i n g material from 20 hours to 45 minutes. When 18-crown-6 was added to a t-butyl alcohol solution con-ta i n i n g potassium t-butoxide and octalone (95) the product r a t i o did not change, only the reaction, time was greatly reduced. This rate enhancement i s not surprising since 18-crown-6 com-plexes with potassium ion and renders the dienolate anion un-3 6 complexed and thus more reactive. When HMPA was employed as solvent i n thi s study the amount of y alkylated product formed decreased from 100% gamma to 20% gamma and 80% alpha. The explanation presented above could now be tested. I f the above " t r a n s i t i o n - s t a t e " explanation i s v a l i d , i t should be possible to further increase the amount of a — a l k y l a t e d product by employing conditions which render the enolate anion (101) more "free" i n HMPA. By using a complexing agent, such as 18-crown-6, i n conjunction with HMPA, one would expect the enolate anion to be very reactive and the amount of a-alkylated product to increase r e l a t i v e to conditions were 18-orown-6 was not present. Thus treatment of octalone (95) with 2 equivalents of potassium t-butoxide and 2 equivalents of 18-crown-6 i n HMPA for 30 minutes at room temperature afforded a product mixture -78-which showed two components by G.L.C. in a r a t i o of 92/8 (entry 7) . Coinjection of thi s mixture with authentic gamma alkylated product showed that the minor component had the same retention time as the gamma alkylated product. 5. Synthetic Application I t has been possible to form the product of gamma alk y l a t i o n exclusively by using bases such as lithium t-butoxide or potassium t-butoxide i n solvents such as THF or t-butyl alco-hol with or without the presence of 18-crown-6. The product of a-alkylation has been r e a l i z e d as the major product when HMPA was employed as the solvent. When 2 equivalents of 18-crown-6 was present i n a HMPA solution containing 2 equiva-lents of potassium t-butoxide, (1.0 mmol ) of octalone (95) was converted almost exclusively into the product of a-alkylation. Most / Conditions (95) 2 eq. 18-Crown-6 .2 eq. K^ -OBu \-HMPA R.T. (104) 92% These re s u l t s are sy n t h e t i c a l l y very useful since i t i s -79-now p o s s i b l e to form the product of gamma a l k y l a t i o n e x c l u -s i v e l y under a v a r i e t y of r e a c t i o n c o n d i t i o n s and the product of a - a l k y l a t i o n , almost e x c l u s i v e l y , under a c e r t a i n s e t of r e a c t i o n c o n d i t i o n s . At no time was the product of a ^ - a l k y l a -t i o n d e t e c t e d . (C) S t r u c t u r a l Assignment of A l k y l a t i o n Products (103) When keto mesylate (95) was s u b j e c t e d to a v a r i e t y o f i n t r a m o l e c u l a r a l k y l a t i o n c o n d i t i o n s the on l y product ob-t a i n e d , i n most cases, was an a, B -unsaturated ketone. The N.M.R. spectrum o f t h i s ketone showed a s i n g l e t 6=5.75 which c o u l d be r e a d i l y a t t r i b u t e d to a v i n y l proton a d j a c e n t t o a c a r b o n y l . The i n f r a r e d spectrum e x h i b i t e d an a b s o r p t i o n a t -80-1675 cm ^ which i s c h a r a c t e r i s t i c of an c^B-unsaturated ketone, On the b a s i s of the above data compound (104) was r u l e d out as a p o s s i b l e product s t r u c t u r e o b tained i n the f i r s t f i v e experiments l i s t e d i n Table I I . However, the s p e c t r a l data d i d not p r o v i d e s u f f i c i e n t i n f o r m a t i o n t o allow one to d i s t i n g u i s h between (103) or (66) as the product s t r u c t u r e . To determine which a ;g-unsaturated ketone was o b t a i n e d i n t h i s study, the . a,B-unsaturated ketone formed i n t h i s study was s u b j e c t e d to d e u t e r a t i o n . I f the a c t u a l product o b t a i n e d i n t h i s study was (103), three deuter-ium atoms would be i n c o r p o r a t e d i n t o the molecule. On the otherhand, i f (66) was the product, only two deuterium atoms would be i n t r o d u c e d . D D D d e u t e r a t e d (66) d e u t e r a t e d (103) To t h i s end, the product was d i s s o l v e d i n 1,2-dimethoxy-ethane-deuterium o x i d e , i n the presence o f a c a t a l y t i c amount of potassium hydroxide and the r e s u l t i n g s o l u t i o n was l e f t to s t i r a t room temperature f o r 3 days. I s o l a t i o n of the product, f o l l o w e d by mass s p e c t r a l a n a l y s i s , showed on l y two deuterium atoms had been i n t r o d u c e d i n t o the molecule. T h i s l a t t e r -81-r e s u l t strongly indicated that compound (66)*, the product of gamma a l k y l a t i o n , was the ^^-unsaturated ketone formed i n this study and not compound (103) the product of a-alkylation. •Compound (66), i s a known compound (see reference 39). -82-EXPERIMENTAL GENERAL — • — ' •— t Melting points, which were determined on a Fisher-Johns melting point apparatus, and b o i l i n g points are uncorrected. U l t r a v i o l e t spectra were measured i n methyl alcohol solution using a Cary, model 14, spectrophotometer. Routine i n f r a r e d spectra were recorded on a Perkin-Elmer Infracord model 710 spectrophotometer. Proton magnetic resonance (^"H N.M.R.) spec-t r a were, unless otherwise noted, recorded i n deuterochloro-form solution on Varian Associates spectrometer A-60, T-60 and/or HA-100, XL-100. Line positions are given i n 6 units with tetramethylsilane as an i n t e r n a l standard; the m u l t i p l i -c i t y , integrated peak areas and proton assignments are i n d i -cated i n parenthesis. High resolution mass spectra were re-corded on an AEI; type MS9, mass spectrometer. G.L.C. analysis was performed on a Hewlett Packard model 5830A g a s - l i q u i d chromatography unit. Microanalyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, University of B r i t i s h Columbia, Vancouver. -83-PREPARATION OF 2-ALLYLCYCLOHEXANONE (80) (80) A s o l u t i o n of cyclohexanone (98 g, 1 mole) and p y r r o l i d i n e (.127.5 g", 1.5 mole") was r e f l u x e d i n benzene f o r 7 hours under a Dean-Stark water s e p a r a t o r . The benzene and excess p y r r o l i d i n e were removed by d i s t i l l a t i o n to y i e l d the crude p y r r o l i d i n e enamine. D i s t i l l a t i o n of the l a t t e r a f f o r d e d pure p y r r o l i d i n e enamine i n 90% y i e l d as a c o l o u r l e s s o i l . b.p. 108-110°C (bath temperature) at 13 mm. To a s o l u t i o n of 125 g of the p y r r o l i d i n e enamine of cyclohexanone i n one l i t e r of a c e t o n i t r i l e was added drop-wise 120 g of a l l y l bromide. A f t e r the a d d i t i o n was complete the s o l u t i o n was r e f l u x e d o v e r n i g h t (18 hours) under n i t r o g e n . A f t e r removal of most o f the a c e t o n i t r i l e , by r o t a r y evapora-t i o n , the r e s i d u e was d i l u t e d w i t h 600 ml of water and heated on a steam bath f o r 30 minutes. The r e s u l t i n g s o l u t i o n was c o o l e d and e x t r a c t e d with e t h e r . The combined e t h e r e x t r a c t s were d r i e d , c o n c e n t r a t e d and d i s t i l l e d under reduced p r e s s u r e to y i e l d ketone (80) (92 g, 66% ) as a colourless liquid; b.p. 100-105°C (bath temperature) at 19mm. -84-PREPARATION OF OCTALONE (82) O (82) A s o l u t i o n o f 3.0 ml o f 3N NaOMe i n ( lOOg, 0.72 mmol) of 2-a l l y l c y c l o h e x a n o n e maintained a t -10°C was e f f i c i e n t l y s t i r r e d under an atmosphere o f n i t r o g e n and ( 54g, 0.77 mmol) of methyl vinyl ketone was added over a p e r i o d o f 2 hours. A f t e r an a d d i t i o n a l 24 hours a t -10°C, the r e s u l t i n g t h i c k creamy r e a c t i o n mixture was t r a n s f e r r e d u s i n g e t h e r and water to a s e p a r a t o r y f u n n e l and thoro u g h l y e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h b r i n e , d r i e d (MgS0 4) and evaporated t o g i v e _ mi80 g o f crude o i l . The i n f r a r e d spectrum showed the presence o f a h y d r o x y l group, a s a t u r a t e d c a r b o n y l a b s o r p t i o n as w e l l as an 0,6 - u n s a t u r a t e d c a r b o n y l a b s o r p t i o n . The e n t i r e crude mix-t u r e was then r e f l u x e d f o r 2 hours i n a 5% sodium methoxide-methanol s o l u t i o n , c o o l e d and n e u t r a l i z e d w i t h g l a c i a l a c e t i c a c i d . The " r e s u l t i n g n e u t r a l s o l u t i o n was evaporated and the r e s i d u e e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed w i t h b r i n e , d r i e d (MgSO^), and evaporated t o g i v e a crude yellow o i l . D i s t i l l a t i o n under reduced pressure afforded ( 50g,72%) of starting material; b.p. 100-105°C (bath temperature) at 19mm, and (46g, 0.242mole) of octalone (82); b.p. 110-115°C (bath temperature) at 0.4 mm. -85-PREPARATION OF ETHYLENE KETAL (83) A s o l u t i o n of ( 5 g, 26.3 mmol ) of octalone (82), (4.6 ml /75.0 mmol ) of ethylene g l y c o l and .1 g of p-toluene-s u l f o n i c acid i n 160 ml of benzene was refluxed f o r 18 hours under a Dean-Stark water separator. The benzene solut i o n was cooled and s o l i d NaHCO^ vas added to neutralize the p-toluene-s u l f o n i c acid. The e n t i r e solution was transferred to a separa-tory, funnel, washed with H^O, dried (MgSO^), and evaporated to y i e l d crude k e t a l (83). D i s t i l l a t i o n under reduced pressure -afforded pure ketal (83) (5.5g, 92%) as a colourless o i l ; b.p. 135-145°C (bath temperature). at 0.5mm; i.r.' (film) X  1 1090 cm-1; p.m.r. 6=5.3 (m,4H, vinyl) , 6=3.9 ( s, 4H, ketal H) . Mol. Wt. Calcd. for C 1 5H 2 20 2: 234.161790. Found (high resolution mass spectrometry) 234.161971 . PREPARATION OF KETAL ALCOHOL (84) r OH <84) To a s t i r r e d s o l u t i o n of { 14.3 ml ,'0.131 mole) 2-methyl-2-butene i n 100 ml of THF at 0° and under an atmosphere of N 2 , was added (6.72ml, 0.065 mole) of a dimethylsulfide-borane complex. After 1 hour at 0° C a solution of octalone (83) (5.0 g, 26.3 mmol. ) i n 4 0 ml THF was added and the reaction mixture was l e f t t o s t i r 2 hours at room temperature. The reaction mixture was once again cooled to 0 ° c and 85 ml of 3N NaOH solution was added dropwise with care, followed by careful dropwise addition of 85 ml of 30% H2°2* T* l e r e a c t ^ - o n mixture w ^ s warmed to room temperature and s t i r r e d for 3 hours then concentrated. The re-s u l t i n g o i l was d i l u t e d with H 20 and extracted with ether. The combined ether extracts were washed with brine, dried (MgSO^), and evaporated to give 5.5 g of crude ke t a l alcohol (84) i n 78% purity by G.L.C. Chromatography on s i l i c a gel and el u t i n g with a petroleum ether-ether mixture afforded (4.6 g , 70% ) of pure ketal alcohol (84) as a colourless o i l . An .'analytical sample 'was obtained try preparative gas liquid chromatography. i . r . (film) * m a x 3450 cm ^ (hydroxyl); p.m.r. 6=5.4 (nijlH, v i n y l ) , 6=4.0 (s , 4H, ke t a l H) , 6=3.6 (m, 2H, CH20H) . Mol.Wt. calcd. for c T_5 H24°3 : 252.1726. Found (high resolution mass spectrometry) ,(252.1726). PREPARATION OF KETAL MESYLATE (85) ( 8 5 ) -87-To an i c e c o l d s o l u t i o n of k e t a l a l c o h o l (84) (3 g, 11.8 mmol ) and methane s u l f o n y l c h l o r i d e (1.5 g,13 mmol- ) i n 80 ml of methylene c h l o r i d e was added dropwise 1.8 g of t r i e t h y l a m i n e (17.7 mmol ). The r e s u l t i n g mixture under a n i t r o g e n atmos-phere was l e f t to s t i r f o r 45 minutes then poured i n t o i c e water. The cold mixture was extracted using methylene chloride, dried (MgSO^) and eva-porated under reduced pressur to y i e l d the crude ketal mesylate , (100) i n 100% y i e l d : i . r , ( f i l m ) x m a v 1450,1350,1170,109 0 cm - 1; p.m.r. 6=5.5 (m, IH, v i n y l ) , 6-4 . 3 (m, 2H , -CH 2-0 Ms) , 6=3.8 (unresolved d o u b l e t ) 4 H , k e t a l H) and 6=3.0 (s,3H,0-S-CH3>. PREPARATION OF KETAL CHLORIDE (86) I C l -(86) A solution of ketal mesylate (85) (3.5 g, 11.8. mmol) and lithium chloride ('2.5 g, 60 mmol ) was refluxed i n acetone for 18 hours. At thi s time the reaction mixture was cooled and evaporated under reduced pressure. The re s u l t i n g residue I was di l u t e d with H 20 and extracted with ether. The combined ether extracts were washed with brine, dried (MgSO^) and evapor-ated to y i e l d crude ke t a l chloride (86), as an o i l (2.55 g) i n 94% y i e l d . An a n a l y t i c a l sample was prepared by column chrom-atography on s i l i c a g e l , eluting with a 50/50 mixture of petro-leum ether/ether: i . r . (film) X a v 1450,1090 cm - 1; -88-p.m.r. 6=5.48 (m,1H,vinyl), 6=3.98 (s,4H,ketal H) , 6 = 3.5 (m,2H,-CH2-C1) . PREPARATION OF OCTALONE (77a) , C l (77a) To a so l u t i o n of ket a l chloride (86) (2.55 g, 9.0 mmol ) i n 20% aqueous acetone was added 0.3 ml of concentrated s u l f u r i c acid and the reaction refluxed for 14 hours. The reaction mix-ture was then cooled neutralized with NaHCO^ and acetone evapor-ated under reduced pressure. The r e s u l t i n g residue was d i l u t e d with F^O and extracted with ether. The combined ether extracts were washed with dried (MgSO^), and evaporated to y i e l d crude a 3-unsaturated keto chloride (77a). Chromatography on s i l i c a g e l , and elu t i n g with a petroleum ether-ether mixture gave (1.9 g, 90% from^-aijof octalone (77a); b.p. 125-135°C (bath temperature) at .03mm; i . r (film) \ 1660 (conj. carbonyl) and 1620 cm - 1 (conj. • "max unsaturation); p.m.r. 6=5.75 (s,IH,vinyl), 6 -3.5 (m,2H, -CH 2-C1). Mol.Wt. calcd. for C 1 3H l gC10: 226.112423. Found (high resolu-t i o n mass spectrometry) 226.111946. -89-PREPARATION OF KETAL IODIDE (87) I A solution of k e t a l mesylate (85) (3.6 mmol ) , sodium iodide (18.0 mmol ) and sodium bicarbonate (4.0 mmol ) in acetone was refluxed for 20 hours. At thi s time the reac-ti o n was cooled and evaporated under reduced pressure. The re s u l t i n g residue was d i l u t e d with E^O and extracted with ether. The combined ether extracts were washed with E^O, brine, sodium t h i o s u l f a t e , U^O, dried (MgSO^) and evaporated to y i e l d crude ke t a l iodide (87): i . r . (film) A 1450, ' max 1240, 1090 cm"1; p.m.r. 6=5.4 (m, IH, vinyl) , 6 -3. 9 (.s, 4H,ketal H) , 6=3.2 (m, 2H,-CH2-I) . PREPARATION OF OCTALONE (77b) I (77b) To a solution of crude ke t a l iodide (87) 0.860 g i n 10% aqueous acetone (40 ml) was added dropwise 0.15 ml of con-centrated s u l f u r i c acid and the reaction mixture was refluxed for 18 hours. The reaction mixture was then cooled, neutralized -90-with s o l i d NaHCO^ and evaporated under reduced pressure. The r e s u l t i n g residue was di l u t e d with 1^0 and extracted with ether. The combined ether extracts were washed with brine, dried (MgSO^) and evaporated to y i e l d iodide (77b) as a white c r y s t a l l i n e compound. R e c r y s t a l l i z a t i o n from petroleum ether-ether afforded the iodide (77b) (350 mg , 30% front the ketal alcohol) as white needles m.p. 60-61°C; i . r . (film) X 1655 (conj. carbonyl), 1615 c m " 1 (ccnj. unsaturation) ; p.cur-. 6= 5.7 (s. , 1H_, vinyl proton) , <S = 3.2 ( m , 2H , Mol.Wt. c a l c d . f o r C 1 3 H 1 9 I : 318.0484. Found (high r e s o l u t i o n mass spectrometry) 318.0482. PREPARATION OF OCTALONE (91)- #1 (entry 2 Table I) propylamide (prepared from 2.2 mmol of diisopropylamide and 2.0 mmol of n-butyl lithium) was added, dropwise, under a nitrogen atmosphere, 1.0 mmol of octalone (77a). The solution was l e f t to s t i r for 3 hours at room temperature then quenched by pouring into 50 ml of 0.1 N HCl solution. The r e s u l t i n g mixture was extracted with ether and ether extracts were washed with H^ O, dried (MgSO^) and evaporated to y i e l d crude octalone (91). Hot box d i s t i l l a t i o n under reduced pressure afforded -<H2-U'. -91-pure octalone (91) as a colourless o i l in 57% y i e l d ; b.p. 115-125°C (bath temperature) at 0.2 mm; i.r.X 1670 c m - 1 ; ^ max (conj. carbonyl), 1620 cm (conj. unsaturation) ; p.m.r.<5= 6.02 ( s, IH, vinyl). Mol.Wt. calcd. for c i 3 H i 8 0 : 1 9 0 ' 1 3 5 7 « Found (high resolution mass spectrometry) 190.1363. CYCLIZATION OF KETO IODIDE (77b) IN t-BUTYL ALCOHOL (entry 9 Table I) (77b) (91) To a solution of potassium t-butoxide (2.0 mmol ) i n t-butyl alcohol at room temperature and under an atmosphere of nitrogen, was added dropwise a solution of octalone (77b) (1.0 mmole) in t-butyl alcohol. The reaction was l e f t to s t i r for 15 minutes and quenched by pouring the reaction mixture int o 50 ml of a 0.1 N HCl solution. The r e s u l t i n g mixture was extracted with ether and the combined ether extracts were washed with H 20, dried (MgS04) and evaporated to y i e l d crude octalone (91). P u r i f i c a t i o n by d i s t i l l a t i o n afforded pure octalone (91) as a colourless o i l i n 94% i s o l a t e d y i e l d . PREPARATION OF OCTALONE (90) (entry 1 Table I) (90) To a solution of potassium t-butoxide (2.0 mmol ) in t-butyl alcohol at room temperature and under an atmosphere of nitrogen was added dropwise a solution of octalone (77a) (1.0 mmol. ) i n t-butyl alcohol. The reaction was l e f t to s t i r at room temperature for 4 hours and quenched by pouring the reaction mixture into 50 ml of a 0.1 N HCl solution. The r e s u l t i n g mixture was extracted with ether and the combined ether extracts were washed with ^ 0 , dried (M^SO^) and evapor-ated to y i e l d a crude o i l . D i s t i l l a t i o n of the crude o i l afforded a product which showed two components i n a r a t i o of 88:12, by g a s - l i q u i d chromatography. The two components were separated by column chromatography using s i l i c a gel and e l u t i n g with a petroleum ether-ether mixture. The major product proved to be the product of . a-alkylation, octalone (90), from the following data. i . r . (film) A m a x 1710 cm - 1 (sat. carbonyl); p.m.r. 5=5.55 (t, IH, v i n y l , J = 2.0 Hz) . Mol.Wt. calcd. for C T ^ H ^ O : 190.1357. Found (high resolution mass spectrometry) 190.1352. -93-Experimental Procedure (Entry 2 Table I) Experimental procedure was as above with the addition of 2.0 mmol of 18-crown-6 and reaction time of only 15 minutes. Entry 3 Table I Experimental conditions were the same as for entry 1 Table I using THF as solvent and not t-butyl alcohol. Entry 4 Table I Experimental conditions were as above with the addition of 2.0 mmol of 18-crown-6 and reaction time of only 15 minutes. Entry 5 Table I Experimental conditions were the same as for entry 1 Table I using HMPA as solvent instead of t-butyl alcohol. Entry 6 Table I A solution of lithium t-butoxide was prepared by adding 2.0 mmol of methyl lithium to t-butyl alcohol under an atmosphere of nitrogen. To the above solution was added drop-wise 1.0 mmol . of octalone (77a) i n t-butyl alcohol. The re s u l t i n g mixture was refluxed for 6 hours and quenched i n the usual manner. Workup afforded a mixture of a and a-alkylated products. Entry 8 Table I Experimental conditions were s i m i l a r to those em--94-ployed for entry 2 Table I, except for the following changes. F i r s t l y the solvent used was a 40:60 mixture of t-butyl alcohol: THF containing 2.0 mmol of 18-crown-6. The s t a r t i n g material was added at -7 8°C and the reaction mixture was allowed to warmup to room temperature over a period of 30 minutes. This was followed by an addit i o n a l 15 minute period of s t i r r i n g at room temperature before the reaction was quenched. Entry 9 Table I Experimental conditions were the same as those employed f o r entry Table I except that the reaction time was only 15 minutes. Entry 10 Table I Experimental conditions were the same as those used i n entry 2 Table I. Entry 11 Table I Experimental conditions were the same as those used i n entry 8 Table I. PREPARATION OF OCTALONE (93) ( 9 3 ) -95-Compound (93) vas prepared from octalone (90) 37 using Barton's Wolff-Kishner conditions es outlined below. Octalone (90) (2.47 mmol ) was allowed to react with 25 ml of a 1.45 K sodium glycolate s o l u t i o n containing anhydrous hydrazine at 165°C-for 12 hours under protection fror, atmospheric moisture. The reaction temperature was raised to 210°C by dis-t i l l i n g excess hydrazine from the v e s s e l . A f t e r r e f l u x i n g f o r an a d d i t i o n a l 8 hours, the cooled s o l u t i o n was d i l u t e d with E^O and extracted with petroleum ether 30-60°C. The organic extracts were combined, washed with I^O, d r i e d (MgSO^) and evaporated under a s p i r a t o r pressure using no heat t o y i e l d a colourless o i l . Distillation under reduced pressure afforded (0.35g, 80.6%) of a colourless o i l ; b.p. 135-140°C (bath temperature) at 7.0mm; i . r . (film) X 1450 cm-1, 1090 cm"1 (no carbonyl) ; p.m.r. 6=5.4 (t, IH, J=2.0 Hz, vinyl H) PREPARATION OF OCTALONE (9 2) 592) Octalone (92) fcras prepared from octalone $93) asing the Collins oxidation procedure as follows. Octalone (93) (.195 Q j l . l l maol ) was dissolved in dichloromethane and was added to a snagnetically stirred red solution containing a 15 fold excess of a 1:1 complex of pyridine and chromium trioxide in -96-dichloromethane. The reaction was l e f t to s t i r for 6 hours at which time i t was f i l t e r e d through c e l i t e and passed through an alumina bed (A c t i v i t y I I I ) . A f t e r d i l u t i o n with H^O, the aqueous phase was drawn o f f and discarded and the organic layer was washed with J^O, 3N HC1 solution, dried (MgSO^) and con-centrated. The r e s u l t i n g residue was d i s t i l l e d under reduced pressure to afford (0.18 g, 85%)- of octalone (92) as a colourless o i l ; b.p.125-135°C (bath temperature) at 0.2mm; i . r . (film) \ 1660 cm ^ (conj. carbonyl) 1620 cm (conj. unsaturation)', p.m.r. 6 = 5.76 (sharp s IH, v i n y l ) . Mol.Wt. calcd. for C 1 3H l gO=190.1357. Found (high resolution mass spectrometry) 190.1357. PREPARATION OF 2-CARBOMETHOXYCYCLOHEXANONE (14 5) COOCH (145) To a s t i r r e d mixture of sodium hydride (30.7 g) and dimethylcarbonate (288 g) i n 500 ml of dioxane was added while under an atmosphere of nitrogen 63 g of cyclohexanone dropwise over a period of 4 hours at a constant temperature of 80-85°C. The solution was l e f t to s t i r an additional 12 hours, cooled and a c i d i f i e d by the slow addition of 10% acetic acid. The solvent was removed under aspirator pressure, the residue was di l u t e d with H„0 and extracted with ether (3x200 ml). The combined -97-ether extracts were washed with r^O, sodium bicarbonate, brine, dried (MgSC>4) and concentrated to y i e l d 87 g of crude product. Vacuum, distillation afforded pure 2-carbomethoxycyclohexanone (85 g, 85% ) as a colourless o i l ; b.p. 105-:107OC (bath temperature ) at 30nm; p.m.r. 6 =1.25 (s, IH enol H ), 6=3.5 (s, '3H, C-O-CH,). PREPARATION OF OCTALONE (97) COOCH 0 (97) To a s t i r r e d solution of sodium methoxide (120 mmol ) (made from 2.76 g of sodium i n 80 ml of CH3OH), at -78°C was added dropwise(15.6 g, 100 mmol ) of 2-carbomethoxycyclohexanone over a period of 5 minutes. After a further 2 minutes of s t i r -r i n g , (8.4 g, 120 mmol ) of methyl v i n y l ketone was added drop-wise. The reaction was allowed to warm up to room temperature over a period of one hour then quenched by pouring i t into some water. The r e s u l t i n g mixture was extracted with carbontetra-chloride and the combined extracts washed with H2O, dried (MgSO^ and concentrated to y i e l d 18.3 g of a crude orange o i l . 1 Vaccuum d i s t i l l a t i o n afforded octalone (97) (18 g, 87%) as a colourless o i l b.p. 160-164°C (bath temperature) at 0,7 jrm; i . r . (film) X 1710 cm-1 ( ester ITlcLX carbanyi), 1680 cm 1 (conjugated carbonyl), 1640 cm-1 (conj. unsaturation); -98-e p.m.r . =5.95 (s, IH, vinyl), <§=5.8 (s, 3H, C-CCH.,) . PREPARATION OF KETAL (9 8) COOCH 3 (98) A solution of (13.6 g, 0.065 mole) Tceto ester (97), (8.0 g , 0.13 mole) of ethylene g l y c o l and 0.200 g of p-toluene-s u l f o n i c acid i n 150 ml of benzene was refluxed for 24 hours under a Dean-Stark water separator. The reaction mixture was then cooled and treated with sodium bicarbonate. The entire reaction mixture was then transferred to a separatory funnel and washed with water. The benzene layer was then dried (MgSO^) and evaporated to give a crude o i l . Vacuum d i s t i l l a t i o n afforded ket a l ester (9 8) (80%) as a slightly yellow o i l ; b.p. 130-140°C (bath temperature) at 0.50 mm; i . r , (film) . X__v 1720 (ester carbonyl) 1080, 980,940 cm"1; p.m.r. 6=5.65 (m,lH v i n y l H), .6=4.0 (s 4H,ketal H) , 6 = 3.7 (s,3H, 0-OCH_3) . Anal. Calcd. f o r c x 4 H 2 o ° 4 : C ' 6 6 - 7 ' H ' 7«9. Found C, 66.48; H, 8.1. PREPARATION OF KETAL ALCOHOL (99) , -OH (99) -99-To a THF s o l u t i o n (120 ml) c o n t a i n i n g (22 g, .094 mole) of ketal ester (98) at 0°C, under , was added in portions, (3.3 g , 86.6 mmol) of L i A l H ^ . The r e a c t i o n was l e f t to s t i r at room temperature • f o r 1 hour and quenched by the slow (dropwise) a d d i t i o n of a NH.C1 s o l u t i o n . A f t e r s u f f i c i e n t NH.C1 was added to g e l a t i n i z e 4 4 the s o l u t i o n i t was then f i l t e r e d through c e l i t e . The f i l t r a t e was evaporated and the r e s i d u e was taken up i n e t h e r - H 2 0 . The e t h e r l a y e r was d r i e d (MgSO^) and evaporated to y i e l d a semi-s o l i d o i l . The a d d i t i o n of petroleum e t h e r - e t h e r mixture c r y s t a l l i z e d the a l c o h o l . R e c r y s t a l l i z a t i o n from petroleum e t h e r - e t h e r a f f o r d e d pure k e t a l a l c o h o l (99)) as a white c r y s -t a l l i n e compound; m.p. 89-91°.C i ^ r . (CHC1-.) x 3500 cm" 1  r i IT , 3 A max (hydroxyl) ; p.m.r. 6=5.1 (m,lH, v i n y l H) , 6 =3.6 (s,4H,ketal H) , ,6=3. 25 ( s,2H,-CH2-OH) . PREPARATION OF KETAL MESYLATE (100) (100) To an i c e c o l d s o l u t i o n o f k e t a l a l c o h o l (99) (2.24 g, 10 mmol' ) and m e t h a n e s u l f o n y l c h l o r i d e (12 mmol ) i n 70 ml of methylene c h l o r i d e was added dropwise, under an atmosphere of n i t r o g e n , 18.0 mmol' of t r i e t h y l a m i n e . The r e s u l t i n g mixture was l e f t to s t i r f o r 45 minutes then poured i n t o i c e water. The cold mixture was extracted with methylene chloride, and the -100-ccmbined extracts were dried (MgSO^ ) and evaporated to yield the crude ketal mesylate ( 3.0 g, 100% ) as an oily solid . Recrystallization from a petroleum ether-ether mixture containing 5% chloroform afforded white needlesjm.p. 102-102.5°C- i . r . (CHC13) ' X m a x 1350, 1170,1090,940 cm - 1. p.m.r. 6=5.6 (m,lH,vinyl H), 6=4.2 (m,2H,-CH2-OMs) , . 6=3. 0 ( s, 3H ,OS-CH3) 6=3.85 (s,4H,ketal H) . Mol.Wt. calcd. for C 1 4H 2 2O 5S=302. . Found (high resolution mass spectrometry) 302.1173. PREPARATION OF OCTALONE (95) (95) i To a solution of ke t a l mesylate (100) ( 3.0 g, 10 mmol ) i n 10% aqueous acetone (60 ml) was added dropwise 1 ml of concentrated s u l f u r i c acid and the reaction mixture was allowed to r e f l u x for 24 hours. The reaction mixture was then cooled, neutralized with sodium bicarbonate, and acetone evapor-ated under reduced pressure. The r e s u l t i n g residue was ex-tracted with ether. The combined ether extracts were washed with brine, dried (MgSO^), and concentrated to y i e l d octalone (95) as a white c r y s t a l l i n e compound i n 68% i s o l a t e d y i e l d . R e c r y s t a l l i z a t i o n from a mixture of carbontetrachloride-hexane containing 5% EtOH afforded white needles of a,3-unsaturated -101-keto mesylate (95) ; in. p. 98-99°C; i . r . (CHCl-J X 1670 cm - 1 j max (co n j . c a r b o n y l ) , 1620 cm""1 ( c o n j . u n s a t u r a t i o n ) , 1350,1170, 980,940 cm - 1; p.m.r. 6=5.8 ( s , l H , v i n y l H), 6=4.33 ( s , 2 H , -CH 2 - 0 M S j , 6 =3.0 (s,3H,OS-CH3) . Mol.Wt. c a l c d . f o r C 1 2H i g0 4S=258. . Found (high r e s o l u t i o n mass spectrometry) 258.0918. PREPARATION OF OCTALONE (66) (66) To a s o l u t i o n o f potassium t - b u t o x i d e (2.0 mole) i n t - b u t y l a l c o h o l a t room temperature and under an atmosphere o f n i t r o g e n , was added dropwise a s o l u t i o n o f o c t a l o n e (95) (0.258g, 1.0 mmol ) i n t - b u t y l a l c o h o l . The r e a c t i o n was l e f t t o s t i r f o r 20 hours and quenched by p o u r i n g the r e a c t i o n mixture i n t o 50 ml of a 0.1 N HC1 s o l u t i o n . The r e s u l t i n g mixture was e x t r a c t e d w i t h e t h e r and the combined e t h e r e x t r a c t s were washed w i t h H^O, d r i e d (MgSO^) and evaporated t o y i e l d a crude ' o i l . The r e s i d u e was d i s t i l l e d under reduced pressure to afford a product (74%) which showed one component by gas liquid chromatography; i . r . (film) A 1660 cm 1 (conj. carbonyl); p.m.r. 6= 5.75 (s, IH, vinyl). Mass spectral peak 162. -102-PREPARATION OF OCTALONE (10 4) (104) To a s o l u t i o n o f potassium t-butoxide (2.0 mmol ) i n 30 ml of HMPA c o n t a i n i n g (2.0 mmol ) of 18-crown-6 was added dropwise 1.1 mmol of o c t a l o n e (95) i n 20 ml of HMPA. The r e a c t i o n , under an atmosphere o f n i t r o g e n , was l e f t to s t i r a t room temperature f o r 30 minutes. The r e a c t i o n mixture was then poured i n t o 50 ml of a 0.1 N HCl s o l u t i o n and e x t r a c t e d (5x50 ml) with pentane. The combined pentane e x t r a c t s were washed (7x50 ml) wit h H,>0 , d r i e d (MgS0 4) and con c e n t r a t e d t o y i e l d a crude o i l . D i s t i l l a t i o n ..under reduced pressure afforded'.a clear o i l which showed 2 components by g a s - l i q u i d chromatography i n a r a t i o o f 92:8. The two components were seperated by p r e p a r a -t i v e g a s - l i q u i d chromatography. The major component (104) had the f o l l o w i n g s p e c t r a l data, i . r . (film) , 1720 cm 1 ( s a t . c a r b o n y l ) ; U.V. ^ ' Amax -1 1 A max 185 MP (£15); p.m.r. 6=5.35 ( t , l H , v i n y l H),6 3.55 ( t , l H , C-C-C=0) , 6 =2.5 ( m,2H,CH2-C=0) . The minor component proved t o be o c t a l o n e ' (66). Experimental Procedure for Reaction Given i n Table II Entry 2 Table II Experimental conditions were as those used for entry 1 ( Table II ) with the addition of 2.0 mmol of 18-crown-6 . Entry 3 Table II Experimental conditions were as those used for entry 1 ( Table II ) except that THF was used as solvent instead of t-butyl alcohol. Entry 4 Table II Experimental conditions involved adding 2.0 mmol of methyl lithium to t-butyl alcohol followed by the dropwise addition of 1.0 mmol of octalone (95). The r e s u l t i n g solution was then refluxed for 20 hours and worked up i n the usual manner. Entry 5 Table II To a room temperature solution of lithium d i i s o -propylamide (prepared from 2.2 mmol- of diisopropylamide and 2.0 mmol of n-butyl lithium) was added dropwise, under an at-mosphere of nitrogen, 1.0 mmol of octalone (95). The r e s u l t i n g solution was s t i r r e d for 2 days at reflux temperature then quenched and worked up i n the usual manner. Entry 6 Table II Experimental procedure was the same as that used for entry 1 Table II except HMPA was employed as solvent i n -stead of t-butyl alcohol and the reaction time was only 30 minutes. -104-DEUTERATION OF OCTALONE (66) deuterated (66) Deuterium oxide was added to a solution of (40 mq, 0.26mmol) octalone (66) i n 1 ml of 1,2-dimethoxyethane u n t i l the mixture was saturated ( .5 ml D^O). A c a t a l y t i c amount of potassium hydroxide was added and the mixture was s t i r r e d at room temper-ature for 3 days. The mixture was then a c i d i f i e d with acetic acid and extracted with ether. The combined ether extracts were washed with r^O, sodium bicarbonate, water, dried (MgSO^), and evaporated to give a crude o i l . D i s t i l l a t i o n under reduced pressure afforded a clear o i l which was subjected to mass spectral analysis. • The mass spectral peak of the undeuterated compound was found to be 162, while the mass spectral parent peak of the deuterated compound was found to be 164. Therefore, compound (66) was established as the product ( a,3-unsaturated ketone) formed i n t h i s study. Mol.Wt. calcd. for c n H i 2 D 2 0 : 164.1164. Found (high resolution mass spectrometry), 164.1170.. -105-PART I I SYNTHETIC STUDY ON ZIZAANE TYPE SESQUITERPENOIDS AND THE TOTAL SYNTHESIS OF (+) ISOLONGIFOLENE INTRODUCTION I. GENERAL REMARKS S t u d i e s i n the area o f terpene chemistry have been very i n s t r u m e n t a l i n g u i d i n g the growth and development of o r g a n i c chemistry as we see i t today. These s t u d i e s have r e -ve a l e d the v a s t a r r a y of molecular a r c h i t e c t u r e s p r e s e n t i n t h i s c l a s s of o r g a n i c compounds which continues to c h a l l e n g e the i n g e n u i t y o f the o r g a n i c chemist. The l a r g e s t group of t e r -penoids, the s e s q u i t e r p e n o i d s , e x h i b i t s the g r e a t e s t v a r i a t i o n of s t r u c t u r a l types, a f a c t o n l y r e a l i z e d i n the past two decades. As l a t e as 1953 onl y about 30 s e s q u i t e r p e n o i d compounds were known; by 1964 th r e e hundred were known, and by 19 71 over one thousand d i f f e r e n t s e s q u i t e r p e n o i d compounds had emerged. T h i s r a p i d i n c r e a s e i n the number o f known s e s q u i t e r p e n o i d s was p a r a l l e l e d by the advent of new a n a l y t i c a l techniques developed i n the l a s t t hree decades. These techniques have f a c i l i t a t e d the d e t e c t i o n , i s o l a t i o n and c h a r a c t e r i z a t i o n of the h i t h e r t o unknown p l a n t compounds and has thus demonstrated t h e i r wide-spread occurrence i n na t u r e . Most s e s q u i t e r p e n o i d s c o n t a i n f i f t e e n carbon atoms and can be hydrocarbons, a l c o h o l s , ketones, a c i d s , o x i d e s , l a c t o n e s and amines. The f i f t e e n carbon atoms can be arranged so t h a t the se s q u i t e r p e n e i s a c y c l i c , mono, d i , t r i or t e t r a -c y c l i c . Because o f the f l e x i b i l i t y i n the carbon s k e l e t o n -106-combined with the v a r i e t y of f u n c t i o n a l groups p o s s i b l e i t i s not s u r p r i s i n g t h a t the s t r u c t u r e s i n the s e s q u i t e r p e n o i d c l a s s of compounds are as widely d i f f e r i n g as f a r n e s o l (107), v e r -n o l e p i n (108) and l o n g i f o l e n e (109). Because of the m u l t i p l i c i t y of s t r u c t u r a l types found i n the s e s q u i t e r p e n o i d c l a s s of compounds any s y n t h e t i c stratagem : used by the o r g a n i c chemist must n e c e s s a r i l y i n v o l v e a s t e r e o s e l e c t i v e approach. Today a r i c h storehouse of knowledge concerning the s t r u c t u r a l and s t e r e o c h e m i c a l course of such r e a c t i o n s as the a l d o l condensation, "Robinson a n n e l a t i o n " r e a c t i o n , e n o l a t e a l k y l a t i o n s and D i e l s - A l d e r r e a c t i o n i s a v a i l -a ble to the o r g a n i c chemist. A p p l i c a t i o n o f the s y n t h e t i c knowledge a v a i l a b l e has l e d to the s u c c e s s f u l s y n t h e s i s of many complex molecules. Below are f o u r such complex molecules, c h l o r o p h y l l (110), r e s e r p i n e (111), c a r y o p h y l l e n e (112) and the p r o s t a g l a n d i n s (113). -107--108-Of the numerous o r g a n i c r e a c t i o n s known, those t h a t p l a y an i n t e g r a l p a r t i n s y n t h e t i c o r g a n i c chemistry i n v o l v e the formation of carbon-carbon bonds. One such r e a c t i o n which was of i n t e r e s t to us i n v o l v e d the formation of a carbon-carbon bond v i a the i n t r a m o l e c u l a r a l k y l a t i o n of an ci^g-unsaturated ketone. I t was our i n t e n t i o n to employ such a r e a c t i o n to form a s u i t a b l y f u n c t i o n a l i z e d molecule which co u l d e a s i l y be t r a n s -formed i n t o a number of n a t u r a l p r o d u c t s . The n a t u r a l products chosen as our o b j e c t i v e i n -cluded i s o l o n g i f o l e n e (114) , a rearrangement product of longi--f o l e n e , as w e l l as z i z a n o i c a c i d (115), zizaene (116), e p i z i z a n o i c a c i d (117) and khusimol (118) which belong to the zizaene c l a s s of s e s q u i t e r p e n e s . I I . THE STRUCTURE AND PREVIOUS SYNTHESIS OF (+) ISOLONGIFOLENE  The f i f t e e n carbon atoms of i s o l o n g i f o l e n e , an a r t e f a c t from the a c i d c a t a l y z e d rearrangement of l o n g i f o l e n e (109), have been shown t o be arranged as d e p i c t e d i n s t r u c t u r e (114). The s t r u c t u r e of (+) i s o l o n g i f o l e n e was determined by 42 43 Dev and co-workers , u s i n g s p e c t r o s c o p i c methods , degradation 44 45 s t u d i e s and f i n a l l y by a c h i e v i n g i t s t o t a l s y n t h e s i s (109) (114) -109-A successful synthesis of (+) isolongifolene has 45 been reported by S. Dev . The f i r s t step in Dev's synthesis of isolongifolene involved the treatment of camphene-l-carboxylie acid (119) with methyl lithium to afford the methyl ketone (120) (119) (120) in 83% y i e l d . Condensation of the methyl ketone (120) with ethyl cyanoacetate i n the presence of ammonium acetate gave the desired d ; 6-unsaturated ester (121) i n 60% y i e l d . Conjugate addition of lithium dimethylcuprate • to (121) afforded (122) as (120) a 'diasteroisomeric mixture i n 80% y i e l d . This mixture -110-was hydrolyzed using potassium hydroxide i n ethylene g l y c o l to y i e l d a single c r y s t a l l i n e acid (123) . The acid (123) was converted into i t s acid chloride which, when treated with SnCl^ i n carbon d i s u l f i d e at -15° C smoothly underwent intramolecular acylation to give c r y s t a l l i n e a}B -unsaturated ketone (124) i n 85% y i e l d . The a^-unsaturated ketone (124) was shown to be i d e n t i c a l with the . a;B unsaturated ketone obtained from the a . l l y l i c oxidation of i s o l o n g i f olene. The above unsaturated ketone was converted into the corresponding d i t h i o k e t a l (using ethane d i t h i o l and BFjEt 20 as c a t a l y s t ) . The d i t h i o k e t a l was refluxed i n the presence of Raney n i c k e l i n ethanol to afford a f t e r p u r i f i c a t i o n an alkene i d e n t i c a l i n a l l respects with (+) iso l o n g i f o l e n e . -111-I I I . THE STRUCTURE AND PREVIOUS SYNTHESES OF SOME ZIZAANE-TYPE SESQUITERPENOIDS  The zizaane group of sesquiterpenoids of which zizanoic acid (115), zizaene (116), epizizanoic acid (117) and khusimol (118)^ 49,51 a r e m e m b e r s f n a s been shown to have the carbon skeleton as depicted below. The structure of t h i s class of sesquiterpenoids was determined by a number of research (115 ) R-^COOH, R„=H (116) R.=CH , R2=H (117) R7=H, R2=COOH (118) Rj=CH OH, R =H -112-groups, using s p e c t r o s c o p i c methods and by a c h i e v i n g t h e i r t o t a l s y n t h e s i s . 4 6 " 4 8 ' 5 1 The Zizaane-type of s e s q u i t e r p e n o i d s c o n t a i n a t r i c y c l i c ( 6 , 2 , l , 0 l f 5 ) undecane system and a number of s u c c e s s f u l syntheses of t h i s carbon s k e l e t o n have appeared i n the l i t e r -52 a t u r e . Coates e t a l . s u c c e s s f u l l y s y n t h e s i z e d (+) zizaane (116) and employed as the key step i n t h e i r s t e r e o s e l e c t i v e s y n t h e s i s , the i n t r a m o l e c u l a r d i a z o a l k a n e - c a r b o n y l r i n g expan-s i o n method (125)—* (126) . (126) R e c e n t l y , an i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n has been used to s y n t h e s i z e a n o r s e s q u i t e r p e n e w i t h the zizaane s k e l e t o n 5 3 (127)-»(128) + (129). -113-Two other successful syntheses of the zizaane-type of sesquiterpenoids both involved a modified pinacol-type rearrangement of a suitably substituted t r i c y c l o (6,2,1,0^'^) undecane, such as (130). The difference between these two sequences l i e s i n the synthesis of compound (130a). Yoshikoski 4 8 et a l . synthesized compound (130a) from (+) camphenoic acid (119a) Rl *2 (130a) R-^H, R2=COOCH3, R3=MeSC>2 (130b) R1=COOCH3, R2=H, R3=MeS02 i n the following manner. The b i c y c l i c alcohol (119c), obtained from the corresponding acid (119a) v i a i t s methyl ester (119b), was oxidized using dicyclohexylcarbodiimide and phosphoric acid (119a) R=H (119c) (131) (119b) R=CH3 i n dimethyl sulfoxide to aff o r d the aldehyde (131) i n 80% y i e l d . -114-Condensation of t h i s material with acetone i n the presence of sodium ethoxide gave the trans-dienone (132). Hydrocyanation of dienone (132) afforded the keto n i t r i l e (133) which, upon treatment with ozone gave the diketo n i t r i l e (134) i n 44% o v e r a l l y i e l d . (170) u When the diketo n i t r i l e (134) was heated with 2 equivalents of benzoic acid and piperidine i n benzene, the k e t o - n i t r i l e (17 1) was formed i n 62% y i e l d . This material was reduced with sodium borohydride and the r e s u l t i n g hydroxy-nitrile was hydrolyzed with potassium hydroxide. The crude reaction product was then treated with diazomethane, followed by Jones 54 oxidation to y i e l d the keto ester (136) i n 74% o v e r a l l y i e l d . The keto-ester (136) was converted into the corresponding -115-CN COOCH. (171) COOCH. (136) COOCH. 74% .(138) COOH (117) (135) COOCH. COOR (139) R=CH. (140) R=H • -116-d i t h i o k e t a l (135) and smoothly d e s u l p h u r i z e d u s i n g Raney n i c k e l to a f f o r d the unsaturated e s t e r (137). O x i d a t i o n of the un-s a t u r a t e d e s t e r (137) w i t h osmium t e t r o x i d e a f f o r d e d the d i o l (138). T h i s d i o l was transformed i n t o the monomesylate (130a) by treatment w i t h m e t h a n e s u l f o n y l c h l o r i d e . The monomesylate 1 5 was smoothly rearranged i n t o the d e s i r e d t r i c y c l o (6,2,1,0 ' ) undecane s k e l e t o n of the zizaene-type of s e s q u i t e r p e n o i d s by treatment w i t h potassium t - b u t o x i d e i n t - b u t y l a l c o h o l . The keto e s t e r (139) was subsequently converted i n t o e p i z i z a n o i c a c i d (117) v i a a W i t t i g r e a c t i o n on the sodium s a l t o f compound (140). Since e p i z i z a n o i c a c i d (117) has p r e v i o u s l y been transformed i n t o z i z a n o i c a c i d (115), khusimol (118) and zizaene (116) the above s y n t h e s i s of e p i z i z a n o i c a c i d a l s o c o n s t i t u t e s a formal s y n t h e s i s o f zizaene s e s q u i t e r p e n o i d s (115)— (118) i n c l u s i v e l y . Q The f o l l o w i n g s y n t h e s i s of the zizaane group of se s -q u i t e r p e n o i d s i n v o l v e s a s i m i l a r rearrangement as t h a t mentioned above but d i f f e r s i n the method of p r e p a r a t i o n o f monomesylate 46 (130a). Thus Ramage e t a l . s y n t h e s i z e d monomesylate (130a) and (130b) from (+)-camphor (141). R e a c t i o n of the l a t t e r w i t h the G r i g n a r d reagent d e r i v e d from 3-bromo-4-methoxytoluene gave a mixture o f a l c o h o l s (142a) and (142b) which upon treatment with s i l i c a r earranged i n t o compound (143). OsO.-NalO, treatment of the l a t t e r a f f o r d e d the 4 4 camphenilone (144) i n 81% y i e l d . B i r c h r e d u c t i o n o f t h i s m a t e r i a l f o l l o w e d by i s o m e r i z a t i o n o f the crude diene, u s i n g t r i p h e n y l -phosphine rhodjum c h l o r i d e i n r e f l u x i n g chloroform, a f f o r d e d the -117-(142a) R ^ A R , R2=OH (143) (142b) R-^OH, R 2=A R conjugated enol ether (202). Ozonolysis of (202) i n ethyl acetate afforded compound (203). Jones oxidation of the l a t t e r gave the diketo ester (204). Base ca t a l y z e d . c y c l i z a t i o n of the diketo ester (204) using potassium t-butoxide i n t-butyl alcohol afforded COOCH 3 COOCH_ (139a) COOH (117) (136a) I COOCH COOH (115) -119-a mixture of t r i c y c l i c enones (136a) and (136) i n the r a t i o of 3:2. This mixture was separated by column chromatography on s i l i c a g e l . E q u i l i b r a t i o n of (136) using potassium t-butoxide in t-butyl alcohol afforded a mixture of (136) and (136a) i n the r a t i o 2:3. Similar r e s u l t s were obtained when compound (136a) was e q u i l i b r a t e d . Having separated the keto esters (136) and (136a) Ramage et a l converted each of the esters into the corres-ponding, monomesylates (130a) and (130b). Rearrangement of the monomesylates afforded the corresponding ketones (139a) and (139b) 1 5 having the required t r i c y c l o (6,2,1,0 ' ) undecane skeleton. These t r i c y c l i c ketones were then converted into epizizanoic acid (117) and zizanoic acid (115) respectively. (115a) Since the methyl ester of zizanoic acid (115a) has already been converted into khusimol (118) and zizaene (116) the above synthesis constitutes a t o t a l s t e r e o s p e c i f i c synthesis of sesquiterpenoids (115) through to (118). The l a s t successful synthesis that I w i l l discuss involves the synthesis of zizaene (115) by K. Wiesner et a l . 5 1 The sequence employed i n t h i s synthesis i s outlined below. The indanol (173) was converted into the phenol (175), v i a the corresponding a l l y l ether (174). Thus, a Claisen rearrangement of the l a t t e r at 185°C afforded the phenol (175). Methylation -120-of the l a t t e r with dimethyl sulfate gave the methoxy derivative (176). Treatment of (176) with sodium chlorate and a c a t a l y t i c amount of osmium tetroxide afforded the d i o l (17 7). Oxidative cleavage of th i s material using sodium periodate gave the alde-hyde (178) which was k e t a l i z e d using ethylene g l y c o l and p — toluenesulfonic acid to afford the corresponding k e t a l (179). Birch reduction of t h i s k e t a l and immediate acid catalyzed hy-- 1 2 1 -d r o l y s i s o f t h e r e s u l t i n g d i e n o l e t h e r ( 1 8 0 ) , p r o d u c e d ( 1 7 9 ) 0 O ( 1 8 0 ) 0 :o ( 1 8 1 ) O I 1 I I ( ^ - u n s a t u r a t e d k e t o n e ( 1 8 1 ) . C y c l i z a t i o n o f t h e 3,Y - u n s a t u r a t e d k e t o n e ( 1 8 1 ) , u s i n g 80% a c e t i c a c i d a f f o r d e d a m i x t u r e o f t h e e p i m e r i c , a , B - u n -s a t u r a t e d k e t o n e s ( 1 8 2 a ) a n d (182b) h a v i n g t h e t r i c y c l i c s k e l e t o n f o u n d i n t h e z i z a a n e c l a s s o f s e s q u i t e r p e n o i d s . (182a) RT=Me, R 2 = H (182b) R ] _ = H , R 2 = C H 3 A l c o h o l (182b) was a c e t y l a t e d u s i n g a mixture of a c e t i c anhydride and p y r i d i n e and the r e s u l t i n g a c e t a t e (183b) was -122-smoothly hydrogenated i n ethanol with palladium-on-charcoal to furnish the keto acetate^ (184b). K e t a l i z a t i o n of t h i s material using ethylene g l y c o l and p-toluenesulfonic acid followed by base hy-d r o l y s i s of the r e s u l t i n g k e t a l (185b),afforded the ketal alcohol(186b Ketal alcohol (186b) was transformed into the ke t a l xanthate (187b) by treatment with carbon d i s u l f i d e and methyl iodide. OH (186b) (188b) OXa (187b) Py r o l y s i s of the ke t a l xanthate (187b) followed by dehydrogena-tio n and deketalization of the r e s u l t i n g unsaturated ketal (188b) afforded the t r i c y c l i c ketone (189b). A l k y l a t i o n of ketone (189b) with p y r o l i d i n e and ethyl bromoacetate followed by base hydrolysis gave the keto acid (190). The sodium s a l t of the keto acid (190) was treated with methylene, \ -123-(190b) triphenylphosphorane to afford the unsaturated carboxylic acid (191b). The acid (191b) was then subjected to the Simmons-Smith cyclopropanation conditions using diiodomethane with a zinc-copper couple to afford the t e t r a c y c l i c carboxylic acid (192b). Hydrogenation of the l a t t e r over Adam's catalyst afforded the gem-dimethyl carboxylic acid (193b). The carboxylic acid (193b) was then subjected to bromodecarboxylation conditions, using,the modified Hunsdiecker method , with bromine and red mercuric oxide to afford the t r i c y c l i c bromide (194b). Dehydrobromination using lithium bromide and lithium carbonate in DMF afforded the tricyclic hy-drocarbon (195) . An identical reaction sequence (182a)->(194a) afforded, after dehydrobromination of (194a), the tricyclic hy-drocarbon (196). A comparison of the hydrocarbons (195) and (196) to zizaene (116) revealed that both compounds (195) and (196) were isomers of zizaene (116). Epizizaene (196) was treated with osmium tetroxide and the resultant diol (197) was oxi-datively cleaved using periodate to furnish ketone (198). The ketone (198) was epimerized in methanolic sodium methoxide to afford the ketone (199) with the natural stereochemistry. The ketone (199) was treated with methyl lithium which afforded a mixture of epimeric alcohols (200a) and (200b). Acetylation of this mixture using acetic anhydride in pyridine afforded the unstable acetates (201a) and (201b), which under the reaction conditions, (160°C, 60 h); pyrolyzed to give racemic zizaene (116). -125-(196) (197) (200a) R1=CH3,R2=OH . ( ) (200b) R1=OH,R2=CH3 (201a) Ri=CH3,R2=OAC (201b) Ri=OAC,R2=CH3 -126-DISCUSSION I. GENERAL APPROACH To be s u c c e s s f u l i n the s y n t h e s i s o f complex molecules i t i s o f t e n u s e f u l t o work the problem backward. Furthermore i t i s o f t e n h e l p f u l t o be g i n the s y n t h e t i c p l a n by f i r s t c a r e f u l l y s t u d y i n g a molecular model of the compound. The c a r -bon s k e l e t o n o f the t a r g e t molecule can then be s i m p l i f i e d by t h e o r e t i c a l l y "breaking" bonds t o form a l e s s complex molecule. The s t r u c t u r a l l y l e s s complex molecule should possess the appro-p r i a t e f u n c t i o n a l i z a t i o n so t h a t i t c o u l d be e a s i l y reassembled back i n t o the o r i g i n a l t a r g e t molecule. Examples of t h i s type of s y n t h e t i c stratagem and methodology can be found i n the 22 l i t e r a t u r e . K e l l y e t a l , i n t h e i r s y n t h e s i s o f (+) ishwarane (51) used t h i s g e n e r a l approach. The t h e o r e t i c a l " breaking" o f the Cp-C,- bond i n (+) ishwarane (51) -127-produced a s i m p l i f i e d t r i c y c l i c structure (49) as compared-.with ishwarane. The appropriately functionalized intermediate (49) underwent an intramolecular a l k y l a t i o n reaction to form the t e t r a c y c l i c skeleton of ishwarane. A s i m i l a r approach, was used i n our synthesis of (+) isolongifolene (114)* and of the zizaane-type sesquiterpenoids. (114) At the outset of t h i s project i t was our intention to construct the t r i c y c l i c carbon skeleton of isolongifolene (114) v i a an intramolecular a l k y l a t i o n reaction of an a .$ -unsaturated ketone. Upon analyzing the structure of isolongifolene i t becomes clear that the t h e o r e t i c a l "breaking" of the bond would lead to a much simpler b i c y c l i c intermediate (144b). This intermediate (144b) * (144a) •Numbering system taken from paper by S. Dev et a l -128-when properly functionalized should c l e a r l y resemble compound (144a). In fac t the compound chosen as the synthetic i n t e r -mediate was keto tosylate (144). I t appeared to be an a t t r a c t i v e TsO choice for a number of reasons. F i r s t l y , i t was a r e l a t i v e l y simple decalone system (ignoring stereochemistry). Secondly, an extended dienolate anion could be generated s p e c i f i c a l l y at the Cg p o s i t i o n . T h i r d l y , molecular models of keto tosylate (144).) indicated that when i n an appropriate conformation, (B ring i h a boat conformation) , C-, and C c are i n very close proximity. (144c) (165) Fourthly, the leaving group i s located on a primary carbon atom and hence should be e a s i l y displaced. F i n a l l y , the reconstruction of the t r i c y c l i c skeleton of isolongifolene would be accomplished -129-v i a the intramolecular a l k y l a t i o n of an a B-unsaturated ketone. If and when octalone (165) i s prepared i t should be "easy" to introduce two t e r t i a r y methyl groups v i a the following four step sequence. U68) At t h i s point i t i s pertinent to focus attention more s p e c i f i c a l l y upon compound (166). This compound i s suitably CN 2) functionalized for the introduction of a n i t r i l e f u n c t i o n a l i t y -130-at the p o s i t i o n . I f hydrocyanation of dieneone (166) i s s u c c e s s f u l i t should form compound (171) or compound (172) or both. I t i s not important which n i t r i l e i s formed s i n c e the corresponding e s t e r s , compound (136) and (136a), have been shown (136) • (136a) to be interconvertible .*° I f a,$-unsaturated keto n i t r i l e (171) i s the product of hydrocyanation of dienone (166) then formation of compound (171) w i l l constitute a formal synthesis of the above mentioned zizaane-type sesquiterpenes for the following reasons. F i r s t l y , a ;B-unsaturated keto n i t r i l e (171) has already been transformed, v i a the <x;Br unsaturated keto ester (136), into 48 epizizanoic acid (117) . Secondly, the l a t t e r compound has been transformed into zizanoic acid (115), zizaene (116) and khusimol (118). I f , on the other hand, the n i t r i l e group i s i n t r o -duced from the 6-face to form a y B-unsaturated keto n i t r i l e (172) i t i s only important to convert the a,$—unsaturated keto n i t r i l e (172) into the corresponding methyl ester (136a) for the following 46 reasons. Ramage et a l have shown that ar& -unsaturated keto (116) -132-ester (136a) can be read i l y transformed into zizanoic acid (115). (17 2) (136a) (115) Secondly, Ramage et a l have demonstrated that base catalysed e q u i l i b r a t i o n of either -.-a,J3-'unsaturated keto ester (136) or (136a) res u l t s i n a mixture of a,3-unsaturated keto esters (136) and (136a) . (136a) '(136) (136a) (136) 2 3 2 3 -133-I I . TOTAL SYNTHESIS OF (±) ISOLONGIFOLENE * The s t a r t i n g m a t e r i a l chosen f o r the s y n t h e s i s of keto t o s y l a t e (144) was o c t a l o n e (97). Octalone (97) was prepared 57 by a known l i t e r a t u r e procedure and showed s p e c t r a l and phys-i c a l p r o p e r t i e s i n accord w i t h the assig n e d s t r u c t u r e . Octa-lone (97) was d i a l k y l a t e d u s i n g methyl i o d i d e i n the presence of 5 8 potassium t-butoxide to g i v e an 80% y i e l d of o c t a l o n e (146). The p h y s i c a l and s p e c t r a l p r o p e r t i e s were i n accord with s t r u c -t u r e (146). The i n f r a r e d spectrum of o c t a l o n e (146) showed ab s o r p t i o n s a t 1730 c m - 1 and 1710 cm 1 due to the e s t e r c a r b o n y l and s a t u r a t e d c a r b o n y l r e s p e c t i v e l y . The ^H N.M.R. spectrum e x h i b i t e d a t r i p l e t a t 6 a5.9 0 due to the v i n y l p r o t o n , and a s i n g l e t a t 6=3.75 due to the methyl protons of the e s t e r group and a s i x proton s i n g l e t a t 6 =1.15 r e a d i l y a t t r i b u t e d t o the protons o f the two t e r t i a r y methyl groups. (97) (146) The s a t u r a t e d r i n g c a r b o n y l o f o c t a l o n e (146) was next used as a "handle" f o r the i n t r o d u c t i o n o f the r e q u i r e d one c a r -bon s i d e c h a i n . As expected the W i t t i g r e a c t i o n o c c u r r e d ~ The total sequence is outlined on the next page. -134-(114) -135-chemiospecifically at the more reactive saturated r i n g carbonyl 59 s i t e . Thus, treatment of octalone (146) with four equivalents of methylene triphenylphosphorane i n dimethyl sulfoxide at room temperature for 1.5 hours afforded, a f t e r p u r i f i c a t i o n , diene (147) as an o i l i n 82% i s o l a t e d y i e l d . (146) (147) The physical and spectra data were i n accord with structure (147). The i n f r a r e d spectrum exhibited absorptions at 1635 cm 1 and 890 c m 1 due to the two double bonds and also showed the lack of an absorption at 1710 cm 1 due to any saturated carbonyl present i n the s t a r t i n g material, octalone (146). The N.M.R. spectrum exhibited an absorption at 6=5.80 due to the v i n y l proton of the t r i s u b s t i t u t e d double bond, an absorption at 6=4.70 due to the two v i n y l protons of the exomethylene group as a multiplet, a s i n g l e t at -6 = 3.60 due to the methyl ester protons and two si n g l e t s at6=1.10 and.6-1.24 due to the protons of the two t e r t i a r y methyl groups. -136-In order to complete the c o n s t r u c t i o n of the r e q u i r e d one carbon chain of keto t o s y l a t e (144), the diene (147) was r e g i o -s e l e c t i v e l y hydroborated a t the exomethylene s i t e 6 0 . T h i s l a t t e r t r a n s f o r m a t i o n was accomplished using disiamylborane i n THF f o l l o w e d by decomposition of the i n t e r m e d i a t e t r i a l k y l b o r a n e u s i n g a l k a l i n e hydrogen per o x i d e to y i e l d a mixture o f compounds th a t was presumed to be an e p i m e r i c mixture o f a l c o h o l s (148) and (149). The p h y s i c a l and s p e c t r a l data were i n a c c o r d w i t h s t r u c t u r e s (148) and (149). A G.L.C. a n a l y s i s of t h i s m a t e r i a l on s e v e r a l columns i n d i c a t e d the presence of two compounds. S e p a r a t i o n of t h i s m a t e r i a l by p r e p a r a t i v e G.L.C. f o l l o w e d by s p e c t r a l a n a l y s i s o f each i n d i v i d u a l component, r e v e a l e d t h a t the two compounds were i n f a c t the a l c o h o l (149) and l a c t o n e (150). S i n c e the N.M.R. spectrum o f the o r i g i n a l mixture e x h i b i t e d the c o r r e c t number of protons (as determined by i n t e g r a t i o n ) l a c t o n i z a t i o n must have o c c u r r e d on the column d u r i n g the G.L.C. -137-analysis. That the hydroboration reaction took place regio-s p e c i f i c a l l y at the exomethylene s i t e was evident from the N.M.R. spectra of both the trans-alcohol (149) and the lactone (150). The "^H N.M.R. spectrum of the lactone (150) showed a t r i p l e t at 6=5.80 (vinyl proton region) which integrated for one proton. The N.M.R. spectrum of the trans-alcohol (149) also exhibited a one proton t r i p l e t (6—5.72) i n the v i n y l pro-ton region. The above data c l e a r l y eliminated the p o s s i b i l i t y that hydroboration had occurred at the t r i s u b s t i t u t e d double bond to form compounds (151) or (152). The assignment of the stereochemistry of the hydroxymethyl side chain i n (149) was based on a t h e o r e t i c a l consideration of the following reactions. Of the two alcohols formed during the hydroboration reaction (148) and (149), only the cis-isomer had the required stereochemistry for l a c t o n i z a t i o n . Therefore, the alcohol i s o l a t e d by preparative G.L.C. must have been the trans-alcohol (149). The inf r a r e d spectrum of alcohol (149) showed the presence of a hydroxy1 function at 34 50 cm 1 and an 0 (151) (152) -138-ester carbonyl absorption at 1720 cm . The H N.M.R. spectrum exhibited a t r i p l e t at £-5.72 (t,IH,vinyl), a s i n g l e t at 5 =3.66 due to the methyl ester protons, and a pai r of singlets at 6=1.01 and ^ 1.07 due to the two t e r t i a r y methyl groups. The i n f r a r e d spectrum of lactone (150) exhibited an absorp-ti o n at 1720 cm - 1 due to the lactone carbonyl and no absorption due to any hydroxyl group. The "^H N.M.R. spectrum exhibited a t r i p l e t at 6=5.80 due to the v i n y l proton, a s i n g l e t absorption at '6=1.12 due to the protons of the two t e r t i a r y methyl groups, no absorption for the protons of a methyl ester, and the AB part of an ABX pattern centered at 6=4.16 and 6 =4.56 due to the two protons on the side chain carbon atom i n the lactone r i n g . The next stage i n the synthesis of the keto tosylate (144) required the introduction of a carbonyl group at the C-3 posi -t i o n of compounds (148) and (149) v i a an a l l y l i c oxidation followed by the removal of the carbomethoxy group. However, before the COOCH (148) (144) (149) f i r s t requirement could be met the hydroxyl group had to be protected since i t would not survive the a l l y l i c oxidation step. Thus, treatment of the o l e f i n i c alcohols (148) and (149) with -139-a mixture of ace t i c anhydride and pyridine for 18 hours at room temperature afforded an epimeric mixture of the desired acetates (153) and (154) i n 97% y i e l d . An a n a l y t i c a l sample • (153) (154) of each of the c i s and trans-acetates was obtained by prepara-t i v e G.L.C. (10% O.V.17). The spectral properties of each isomer was i n accord with the assigned structures. Of p a r t i c u l a r i n t e r e s t was the absence of hydroxyl absorptions i n the i n f r a r e d spectrum. The N.M.R. of the respective acetates (153) and (154) exhibited acetate methyl proton resonances as sin g l e t s at 6=2.00 (trans-acetate) and 6=2.04 (cis-acetate). To e s t a b l i s h which isomer was c i s and which isomer was trans, the N.M.R. spectrum of each acetate was compared with that of the trans-alcohol (149) . The "''H N.M.R. of the mixture of alcohols (148) and (149) as well as the ''"H N.M.R. spectrum of the mixture of acetates (153) and (154) both exhibited the same pattern due to t e r t i a r y methyl protons, which appeared as four s i n g l e t s . Of the four s i n g l e t s , two were due to the trans-isomer and two were due to the cis-isomer• The methyl sig n a l patterns are shown below. -140-2.0 1.0 6 ' 6 ; Mixture of alcohols (148)-& (149) trans-Alcohol (149) Mixture of acetates (153) & (154) trans-Acetate (153) cis-Acetate (154) 0.0 The acetate epimer which possessed the same pattern due to the methyl signals as was found for the trans-alcohol (149) was te n t a t i v e l y assigned the trans-stereochemistry (153). To con-firm the above assignment a small sample of the trans-acetate (153) was subjected to base hydrolysis. The r e s u l t i n g alcohol was found to be i d e n t i c a l with the trans-alcohol (149) obtained from the hydroboration reaction. This l a t t e r r e s u l t confirmed the above assignments for the c i s and trans-acetates. The mixture of acetates (153) and (154) was subjected to C o l l i n s oxidation conditions^* 1 i n order to introduce a carbonyl group at the a l l y l i c p o s i t i o n . Although the C o l l i n s oxidation procedure was somewhat successful, providing a mixture of octa--141-NBS,CaCC>3 —+ (155) + (156) lones (155) and (156) i n 70% y i e l d * , a higher y i e l d i n g a l l y l i c oxidation method was sought due to the d i f f i c u l t y involved i n the separation of s t a r t i n g material from product. Thus, 6 2 following the procedure of Thomson et a l a mixture of acetates (153) and (154) was treated with N-bromosuccinimide i n aqueous dioxane, and the resultant mixture was i r r a d i a t e d with v i s i b l e l i g h t . This procedure afforded a mixture of octalones (155) and (156) i n 96% y i e l d . An a n a l y t i c a l sample of both the c i s and trans isomers were obtained by preparative G.L.C. (10% O.V.17). The spectral properties of the octalones (155) and (156) were i n accord with the assigned structures. Thus the in f r a r e d spectrum showed an cx^  8-unsaturated carbonyl absorption at 1660 cm 1 •based on recovered s t a r t i n g material and 1670 cm x for octalones (155) and (156) respectively. The "''H N.M.R. spectrum of the trans-octalone (155) exhibited a si n g l e t at 6=6.22 due to the v i n y l proton and the spectrum of the cis-octalone (156) also exhibited a si n g l e t at 6=6.22 due to the v i n y l proton. The mixture of octalones (155) and (156) upon being sub-6 3 jected to decarbomethoxylation conditions using a f i v e f o l d excess of lithium bromide i n HMPA at 140° for four hours, afforded, after d i s t i l l a t i o n , a clear o i l i n 79% y i e l d . A G.L.C. analysis of th i s o i l indicated the presence of three com-pounds. The spectral data of the mixture indicated that no acid f u n c t i o n a l i t y (I.R.) or ester f u n c t i o n a l i t y (^ H N.M.R.) was present and thus strongly suggested that the three compounds were octalones (157), (158) and (159) . H K e t a l i z a t i o n of the above crude keto acetate mixture using ethylene g l y c o l i n the presence of a c a t a l y t i c amount of p-t o l u -enesulfonic acid afforded the c r y s t a l l i n e ketal (160), m.p. -143-101-102°C i n 87% y i e l d . Compound (160) exhibited absorbances (160) i n i t s i n f r a r e d spectrum at 1725 cm due to the acetate carbonyl and at 1220 cm - 1 due to C-0 bond stretchings. The 1H N.M.R. spectrum of keta l (160) showed a s i n g l e t at 6-3.92 due to the ethylene k e t a l protons; and a multiplet centered at 6-4.00 due to the protons on the carbon bearing the acetate function. The N.M.R. spectrum also showed a s i n g l e t at 6=2.00 which was rea d i l y assignable to the acetate methyl protons and 2 quaternary methyl signals at 6=1.03 and 6=0.87. The above spectral data was i n complete agreement with structure (160). The reduction of ke t a l acetate (160) to the ket a l alcohol (161) was achieved by using lithiu m aluminum hydride i n THF. The s p e c t r a l data of the r e s u l t i n g alcohol (94% yield) were i n accord with i t s proposed structure. The presence of an hydroxyl group was evident due to an absorption at 3350 cm 1 i n the i n f r a -red spectrum. The N.M.R. spectrum of ketal alcohol (161) exhibited a four proton s i n g l e t at 6=3.95 due to the ethylene k e t a l protons, and 2 si n g l e t s at 6= 1.03 and 6= 0.82 due to the two t e r t i a r y methyl protons. -144-(161) (162) Ketal alcohol (161) was next converted into the ke t a l tosylate (162) by the action of p-toluenesulfonyl chloride i n pyridine at room temperature for 12 hours. The crude product upon cooling c r y s t a l l i z e d to y i e l d a f t e r r e c r y s t a l l i z a t i o n , from petroleum-ether/acetone,white needles of keto tosylate (162) i n 99% y i e l d . The s p e c t r a l data were i n agreement with structure (162). Of importance was the absence of a hydroxyl absorption i n the in f r a r e d . The N.M.R. spectrum, which was p a r t i c u l a r l y informative, exhibited an &2*2 P a t t e r n ^ u e t o t n e aromatic pro-tons, a s i n g l e t $=3.90) due to the ethylene ke t a l protons, a s i n g l e t (6=2.42) due to the aromatic methyl group and two sing-l e t s (6=0.95 and 6=0.79) attributed to the t e r t i a r y methyl groups. The c r u c i a l keto tosylates (144) and (16 3) or both could now be obtained from ke t a l tosylate (162) by simply removing the ethylene ketal group and thus regenerating the carbonyl group. Thus, k e t a l tosylate (162) upon treatment with a c a t a l y t i c amount of concentrated s u l f u r i c acid i n aqueous acetone at 50° C (162) (163) H (144)' for 0.75 hours afforded keto tosylate (163) i n greater than 99% y i e l d . The spectral data was.consistent with the assigned structure. The in f r a r e d spectrum exhibited an absorption at 1715 cm 1 due to the saturated carbonyl group. Although the inf r a r e d also exhibited a weak absorption at 1660 cm 1 no v i n y l proton due to an a ; B-unsaturated ketone was detected i n the "*"H N.M.R. spectrum. The "*"H N.M.R. spectrum exhibited and &2X2 P a t t e r n (6-7.3 and 6=7.7) due to the aromatic protons, a multipl e t (6=3.85) due to the two protons on the carbon atom bearing the tosylate group, a s i n g l e t (J = 2.42) due to the aromatic methyl group, and two sin g l e t s (.6=0.70 and 6=0.60) due to the t e r t i a r y methyl groups. That keto tosylate (163) obtained i n the l a t t e r reaction was d i f f e r e n t from the "desired" keto tosylate (144) was of no consequence since during the c r u c i a l c y c l i z a t i o n step both tosy--146-H (165) lates must form the same extended dienolate anion (164). Having thus obtained the keto tosylate (163) the c r i t i c a l (proposed) intramolecular c y c l i z a t i o n of (163) to form the t r i -c y c l i c skeleton of (+) isolongifolene (114) could now be tested, and was, i n fa c t , found to be extremely f a c i l e . Thus treatment of the keto tosylate (163) with potassium t-butoxide i n HMPA at room temperature for 15 minutes afforded, aft e r r e c r y s t a l l i z a t i o n the t r i c y c l i c octalone (165) as white c r y s t a l s m.p. 63-64° C i n 64% i s o l a t e d y i e l d . The spectral data were i n accord with the assigned structure f o r octalone (165) . The "''H N.M.R. spectrum exhibited a sharp s i n g l e t at <S=5.72 readi l y a t t r i b u t e d to the v i n y l proton and a s i x proton s i n g l e t at 6=1.36 due to the two -147-(165) t e r t i a r y methyl groups. The i n f r a r e d spectrum e x h i b i t e d an a ;6 -unsaturated c a r b o n y l a b s o r p t i o n a t 1670 cm - 1. The s p e c t r a l data was i n complete agreement wi t h s t r u c t u r e (165). Having s y n t h e s i z e d o c t a l o n e (165) which possessed the r e q u i r e d f u n c t i o n a l i t y i n the B - r i n g o f (±) i s o l o n g i f o l e n e (114) a l l t h a t remained was to i n t r o d u c e 2 t e r t i a r y methyl groups a t C - l and to remove the c a r b o n y l group. The i n t r o d u c t i o n o f both methyl groups was accomplished by the conjugate a d d i t i o n of l i t h i u m dimethyl cup r a t e t o an ci^ B -un-s a t u r a t e d c r o s s conjugated dienone. Thus the f i r s t step i n the l a s t p a r t of the s y n t h e s i s of (±) i s o l o n g i f o l e n e r e q u i r e d the i n t r o d u c t i o n o f an other double bond in ring A of octalone (]65). 64 T h i s was accomplished by u s i n g d i c h l o r o d i d y a n o q u i n o n e (DDQ) -148-Thus treatment o f o c t a l o n e (165) w i t h 1.5 e q u i v a l e n t s of DDQ i n r e f l u x i n g dioxane c o n t a i n i n g a c e t i c a c i d f o r 17 hours, a f f o r d e d , a f t e r p u r i f i c a t i o n and r e c r y s t a l l i z a t i o n from p e t r o -leum e t h e r , the c r o s s conjugated ketone (166) i n 60% y i e l d as a white c r y s t a l l i n e compound m.p. 72-73 ° C . (166) The s p e c t r a l data were i n accord w i t h s t r u c t u r e (166). The i n f r a r e d spectrum e x h i b i t e d a b s o r p t i o n s a t 1660 cm-'1', 1630 cm - 1 and 1601 cm" 1 f o r the c r o s s conjugated dienone. The "*"H N.M.R. spectrum e x h i b i t e d a doublet a t 6=5.99 ( J _ ,=2 Hz, IH), a doublet a t J6=7.02 ( J 1 2=10 H Z , IH) and a doublet of doublets c e n t e r e d a t 6=6.30 ( J 2 3=2 Hz, J ^ 2 = 1 0 H z ' w n i c h were r e a d i l y a s s i g n e d t o the v i n y l p r o t o n s . A l s o p r e s e n t were two s i n g l e t s a t 6=1.06 and 6=1.11 due to the quaternary methyl groups. When the c r o s s conjugated dienone (166) was t r e a t e d w i t h l i t h i u m d i m e t h y l c u p r a t e 6 ^ a r e g i o s p e c i f i c m e t h y l a t i o n o c c u r r e d to produce the o^g-unsaturated ketone (167) i n 88% y i e l d . T h i s r e s u l t was not a l t o g e t h e r unexpected s i n c e i t has been shown t h a t the conjugate a d d i t i o n o f cuprate reagents w i l l f a v o r a sec-ondary o l e f i n i c s i t e over a s i m i l a r t e r t i a r y o l e f i n i c s i t e . 6 ^ -149-(166) r The stereochemistry of the recently introduced methyl group was assigned with the help of molecular models. These models suggested that the approach of a cuprate reagent from the a face would be severely hindered by the two carbon bridge 0 whereas an attack by the reagent on the g face would encounter less s t e r i c hindrance from the one carbon bridge. The i n f r a r e d spectrum of octalone (167) showed absorptions at 1650 cm"1 and 1640 cm 1 due to the a,3 -unsaturated ketone. The 1H N.M.R. spectrum exhibited a s i n g l e t at 6 =5.72 (IH) due to the v i n y l proton, two si n g l e t s at <5=1.12 and<5-1.08 at t r i b u t e d to the two t e r t i a r y methyl groups and a doublet atgj =1.02 (J=8 Hz) due to the secondary methyl group. The above 2 step sequence was now repeated on octalone (167) i n the hope of introducing a second methyl group at C - l . How-ever, treatment of octalone (167) with DDQ, under a var i e t y of conditions, afforded a very poor y i e l d of dienone (169) and another synthetic sequence was attempted. The d i f f i c u l t i e s encountered i n the dehydrogenation of octalone (167) were overcome when a bromination-dehydrobromination sequence proved somewhat successful. Thus bromination of (168) O 0 (167) (169) 66 octalone (167) using pyridinium hydrobromide perbromide i n THF containing a c e t i c acid at 45°C for one hour afforded the crude bromooctalone (16 8). Because of the unstable nature of the crude bromooctalone mixture, (as indicated by decomposition during d i s t i l l a t i o n ) i t was dehydrobrominated without p u r i f i c a t i o n . Thus, the crude bromooctalone upon treatment with a lithium 6 7 bromide-lithium carbonate mixture i n dimethyl formamide .at 140 wCfor 3 ho urs afforded, af t e r column chromatography ( s i l i c a g e l ) , dienone (169) i n 40% y i e l d . The spectral data were i n agreement with structure (169). The i n f r a r e d spectrum exhibited absorptions at 1660 cm \ 1630 cm 1 due to the cross conjugate dienone. The 1H N.M.R. spectrum exhibited a doublet at 6=6.00 ^ J l 2 = 2 H z ^ d u e t o t h e v ^ n Y 1 proton marked H^ and a p a i r of overlapping doublets centered at 6=6.14 (J=2 Hz) due to the v i n y l proton marked H,,. The v i n y l methyl signal at 6=2.00 (J=2 Hz) appeared as a sharp doublet (J=2 Hz) undoubtedly due to a l l y l i c coupling to H2. The t e r t i a r y methyl groups appeared as singlets at 6=1.10 and $=1.20. -151-(169) Although the bromination-dehydrobromination sequence wasi poor y i e l d i n g , enough material was synthesised to accomplish the f i n a l methyl cuprate addition reaction. Thus treatment of the dienone (169) with 5 equivalents of lithium dimethylcuprate i n ether at room temperature for 5 hours afforded aft e r chromato-graphy, a pure c r y s t a l l i n e sample of octalone (124), m.p. 53-54°c ( i n 40% y i e l d . * The spectral data were i n general agreement with O (124) *based on recovered s t a r t i n g material -152-the l i t e r a t u r e values.** 3 The XH N.M.R. spectrum e x h i b i t e d a s i n g l e t at 6=5.70 due to the v i n y l proton and 4 s i n g l e t s a t 6=1.00, 6=1.05, 6. =1. 09, and 6 = 1.14 due to the fo u r t e r t i a r y methyl groups. Comparing these chemical s h i f t s with the l i t e r a t u r e v alues of 6=5.67, 6=0.99, 6=1.03, 6 =1.08 and 6=1.15 i n d i c a t e d t h a t o c t a l o n e (170) s y n t h e s i z e d by the above sequence was indeed 45 the same as the oc t a l o n e s y n t h e s i z e d by S. Dey e t a l i n t h e i r t o t a l s y n t h e s i s of (±) i s o l o n g i f o l e n e . * The l a s t chemical o p e r a t i o n needed to complete the t o t a l • s y n t h e s i s of (+) i s o l o n g i f o l e n e , the removal of the carb o n y l group of o c t a l o n e (124), was not necessary s i n c e t h i s t r a n s -45 formation had alre a d y been accomplished . T h e r e f o r e the above sequence l e a d i n g t o o c t a l o n e (124) c o n s t i t u t e s a formal t o t a l s y n t h e s i s of (+) i s o l o n g i f o l e n e (114). • S l i g h t d i f f e r e n c e s i n H N.M.R. c o u l d be accounted f o r s i n c e the above measurements were taken i n CDC1 3 w h i l e the l i t e r a t u r e v a l u e s were taken i n CC1.. The change i n s o l v e n t i s known to vary chemical s h i f t s s l i g h t l y 6 9 . However, when o c t a l o n e (124) was remeasured i n CCl.the chemical s h i f t s matched. -153-III AN APPROACH TO ZIZAANE-TYPE SESQUITERPENOIDS To gain access to the zizaane class of sesquiterpenoids we now turned our attention to the dienone (166). As mentioned e a r l i e r i t was our intention to convert the dienone (166) into the n i t r i l e (171) v i a a hydrocyanation reaction. This trans-formation, i f successful, would provide a quick entry into the, CN Zizaane Class (166) (171) zizaane class of sesquiterpenes since octalone (17%) has a l -ready been converted into a number of members of t h i s family of compounds. Treatment of the dienone (166) with a 6 f o l d excess of 6 8 d i e t h y l aluminum cyanide i n benzene for 16 hours at room temper-ature afforded a f t e r preparative thin layer chromatography, the n i t r i l e octalone (172). The spectral data were i n accord with structure (172). The i n f r a r e d spectrum exhibited absorption at 2250 cm ^, which was assigned to the n i t r i l e moiety, and an absorption at 1670 cm 1 due to the a ;8-unsaturated ketone. From a consideration of the H^ N.M.R. spectrum i t was possible to assign the stereochemistry of the n i t r i l e group. A molecular -154-model study of compound (172) indicated that H and H are CN (172) symmetrically disposed with respect to H and therefore should give r i s e to an A 2X system. This proved to be the case. The N.M.R. spectrum showed a t r i p l e t at 6=3.32 (H x; J=3.5 Hz), a sharp s i n g l e t at 6=5.86 (IH, v i n y l proton), a doublet at 6-=2.68 (HA,HB,J=3.5 Hz) and two high f i e l d s i n g l e t s at .6 =1.16 and 6=1.20 due to the two t e r t i a r y methyl protons. Having the n i t r i l e (172) in hand, i t was now necessary to convert t h i s n i t r i l e into the corresponding methyl ester. Un-fortunately due to the lack of s t a r t i n g material, (dienone (166)), the synthesis of octalone (136a) was not carr i e d out. COOCH -155-Thus, i n conclusion, the introduction of a n i t r i l e f u n c t i o n a l i t y into the dienone (166) proved to be stereoselec-t i v e , providing the n i t r i l e (172) with the natural stereochemistry as found i n the zizaane class of sesquiterpenes. An a t t r a c t i v e and novel route to t r i c y c l o (6,2,1,0 1 , 6) undecane systems has been developed culminating i n the t o t a l synthesis of (±) isolongifolene and has provided a short and hopefully a f e a s i b l e entry i n t o the zizaane class of sesquiterpenoids. -156-EXPERIMENTAL PREPARATION OF OCTALONE (14 6) COOCH COOCH i ~> (97) (146) T o a s t i r r e d s o l u t i o n o f p o t a s s i u m t - b u t o x i d e ( p r e -pared from 19.0 g of potassium metal i n 600 ml of t - b u t y l a l c o h o l ) , under an atmosphere o f N 2 was added dropwise at 35°C,(34.0 g, 0.16mole) c oc t a l o n e (97), over a p e r i o d of 15 minutes. The s o l u t i o n was then c o o l e d u s i n g an i c e bath, f o r 5 minutes, a t which time ( 140 g, 1.0 mcle ) of f r e s h l y d i s t i l l e d methyl i o d i d e was added. The r e -s u l t i n g mixture was allowed to r e f l u x f o r 1.5 hours and then c o n c e n t r a t e d . The milky r e s i d u e was d i l u t e d w i t h H2O, n e u t r a l i z e d w i t h h y d r o c h l o r i c a c i d and e x t r a c t e d w i t h e t h e r . The combined et h e r e x t r a c t s were washed w i t h ^ 0 , aqueous sodium t h i o s u l f a t e , b r i n e , d r i e d (MgSO^) and evaporated t o y i e l d 32 grams o f crude o i l . D i s t i l l a t i o n under reduced p r e s s u r e a f f o r d e d (31 g,'80%) dure octalone (146) as a clear o i l ; b.p. 118-122°C (bath_tPJiropj-atur )^ at -1 -1 0.4 mm ; ±.r. (film) X 1710 cm (s a t . c a r b o n y l ) , 1730 cm (es t e r c a r b o n y l ) ; p.m.r. 6-5.90 ( t , l H , v i n y l , J=4.0 Hz)6 =3.75 (s , 3Hf-C-0-CH,) 6 1 5 ( S, 6H, t e r t i a r y methyls) . PREPARATION OF DIENE (14 7) COOCH A s t i r r e d suspension of sodium h y d r i d e (4.8 g, 0.2 mole ) i n 250 ml of dry dimethyl s u l f o x i d e was sl o w l y heated under an atmosphere of n i t r o g e n a t 75°C and kept at t h i s temper-ature u n t i l f r o a t h i n g had ceased (1.5 h ) . The r e a c t i o n mixture was then c o o l e d to room temperature and a s o l u t i o n of methyl triphenylphosphonium bromide (75 g, 0.21 mole), i n 350 ml of dimethyl s u l f o x i d e was added dropwise. The r e s u l t i n g mixture was s t i r r e d f o r 15 minutes, a t which time a s o l u t i o n o f the keto e s t e r (146) (10 g, 0.042 mole ) i n 200 ml of dimethyl s u l f o x i d e was added dropwise. The r e a c t i o n mixture was l e f t t o s t i r an. a d d i t i o n a l hour and then quenched by the a d d i t i o n o f 600 ml of water. The r e s u l t i n g mixture was e x t r a c t e d w i t h petroleum-ether and the combined e x t r a c t s were washed wi t h b r i n e , d r i e d (MgSO^) and evaporated to g i v e a crude o i l . D i s t i l l a t i o n under reduced p r e s s u r e a f f o r d e d (8.0 g, 83%) of pure diene (147); b.p. 120—125°C '(bath tenperature) at o.35nm; i . r . (fi.lrrti X 1735 cm - 1 ( ester . • max c a r b o n y l ) , 1640, 1655, 890 cm 1 (unsaturated C=C); p.m.r. 6=5.80 ( t , l H , v i n y l H, J=4.2 Hz)6-4.70 (d of d,2H,vinyl H, J= 6.0,1.0) 6-3.67 (s , 3H,-C-OCH3)y$ -1.13 (s , 3H, t e r t i a r y methyl), 5* 1.2 8 (s , 3H, t e r t i a r y m e t h y l ) . A n a l . C a l c d . f o r C 1 C H 0 0 0 0 : C, 76.88; H, 9.46. Found: -158-C, 76.97; H, 9.60. PREPARATION OF ALCOHOL (14 8) and (149) To a s t i r r e d solution of (2.6 g, 37.0 mmol) 2-methy-2jbutene in 40 ml of dry THF at 0CC and under an atmosphere of nitrogen was added 14.5 ml of a 0.62 molar diborane solution in THF. . After s t i r r i n g for 1 hour at 0°C a solution of diene (147) (9.0 mmole) in 40 ml THF was added and the reaction mixture was l e f t to s t i r 2.0 hours at room temperature. The reaction mixture was once again cooled to 0° and 12 ml of 3N sodium hydroxide was care-f u l l y added followed by the c a r e f u l addition of 12 ml of 30% hydrogen peroxide. The r e s u l t i n g mixture was s t i r r e d for 1.5 hours at room temperature and concentrated. The r e s u l t i n g residue was d i l u t e d with water and extracted with ether. The combined ether extracts were washed with brine, dried (MgSO^), and evaporated to give a crude o i l . D i s t i l l a t i o n under reduced pressure afforded (l.9g, '84%) of a mixture of the alcohols (14 8)and (149) ; b.p. 130-140°C (bath temperature) at 0.35 mm; G.L.C. analysis on sevoVal solumns showed two compounds. AH N.M.R. spectrum showed a mixture of alcohols. G.L.C. c o l l e c t i o n on 10% O.S. 38 afforded the trans-alcohol (149) plus the c r y s t a l l i n e lactone (150) *, m.p. 79-80°C. Spectral properties of the trans-alcohol (149) -159-COOCH (149) (150) are as follows: i . r . (film) X 3450 cm 1 (hydroxyl), 1725 cm 1 ] max (ester carbonyl); p.m.r. 6 =5.72 (t,l H , v i n y l H, J=4 Hz), 3.66 fe, 3H,-CO-CH_3), 3. 50, 3. 75 (AB part of an ABX system, 2H,-CH2-OH, J A B = 12 Hz, J f i x=5 Hz, J A X=8 Hz). Anal. Calcd. for C 1 5 H 2 4 0 3 : C, 71.39; H, 9.59. Found: C, 71.20; H, 9.76. Spectral properties of lactone (150) •, i . r . (CHC13) X 1720 cm - 1 (lactone carbonyl); p.m.r. 6=1.22 (s , 6H, t e r t i a r y max methyls), 4.10, 4.56 (AB part of an ABX pattern, 2H, -C-0-CH_2-, J A B = 1 2 H Z ' J A X = 4 H Z ' J B X = 2 H Z ) -Anal. Calcd. for C 1 4 H 2 q 0 2 J C, 76.33; H, 9.15. Found: C, 75.90; H, 9.33. PREPARATION OF THE ACETATES (153) and (154) GOOCH. COOCH. OAc (153) (154) -160-A mixture of 10 g of the alcohols (148) and (149) 20 ml of acetic anhydride and 40 ml pyridine was heated over a steam bath for 2 minutes and l e f t standing at room temperature for 18 hours. The reaction mixture was then di l u t e d with water and extracted with ether. The combined ether extracts were washed with IN hydrochloric acid, water, sodium bicarbonate, water, brine, dried (MgSO^) and evaporated to give a crude o i l . D i s t i l l a t i o n under reduced pressure afforded (4.0 g, 94%) of acetates (153) and (154); b.p. 125-130 (bath temperature) at 0.55 mm. G.L.C. c o l l e c t i o n on 10% O.V. 17 at 240° afforded a n a l y t i c a l samples of t r a n s — acetate (155)1 i . r . (film) i 1740, 1720 cm - 1 (ester carbonyls); > * max p.m.r.6 =0.98 ( s,3H,tertiary methyl), 1.05 (s, 3H,tertiary methyl), 2.00 ( s, 3H,0-C-CH3) , 3.62 fe.. 3H, -C-OCH3) , 4.10, 3.86 (AB part of ABX pattern,2H /-CH 2-OAc r J A B=10.0 Hz, J A X=5.0 Hz, Jfix=6.0 Hz). Anal. Calcd. for C,_H_rO. : C, 69. 36; H, 8.90. Found: C, 69.10; LI ZD 4 H, 9.10. Spectral data for the cis-acetate i s as followsJ i . r . (film) X 1740, 1720 cm - 1 (ester carbonyls); p.m.r. max J 6=0.80 (s,3H,tertiary methyl) , 1.19 (s,3H,tertiary methyl), 2.04 ( s, 3H,OC-CH3) , 3.64 ( s, 3H,COCH_3) , 3.8, 4.3 (AB part of ABX pattern, 2H,-CH_2-CAc) , J A B=14 Hz, J A X=4.7 Hz, J B X=4.7 Hz). Anal. Calcd. for C 1 7 H 2 6 ° 4 : C, 69.36; H, 8.90. Found: C, 69.31; H, 8.78. -161-PREPARATION OF OCTALONE (155) AND (156) O (155) COOCH O-(156) L C To a s t i r r e d solution of (4.1g, 13.9 mmol) of a mixture of acetates (153) and (154) i n 250 ml of dioxane was added (7.4g, 41.7 mmol) of N-bromosuccinimide, (2.8g, 27.8 mmol) of calcium carbonate, and 22ml of water. The reaction mixture was allowed to s t i r at room temperature while being exposed to dir e c t v i s i b l e l i g h t (lamp) for 20 hours. The reaction mix-ture was then f i l t e r e d through c e l i t e and the f i l t r a t e extracted with ether. The combined ether extracts were washed with water, sodium t h i o s u l f a t e , brine, dried (MgSO^) and evaporated to y i e l d a crude o i l . D i s t i l l a t i o n under reduced pressure afforded (4.1g, S a mixture of octalones (155) ana (156);b.p. 165-170 (bath temperature) at _ 0.25 mm. . An a n a l y t i c a l sample of each epimer was co l l e c t e d on 10% O.V. 17 at 240°C. The trans-acetate (155) had the following spectral and physical data} i . r . (film) A m a x 1720, 1700 cm - 1 (ester carbonyls), 1660 cm 1 (conj. carbonyl)J p.m.r. *=1.12 (s, 3H, t e r t i a r y methyl) ^  1.18 (S,3H, t e r t i a r y methyl) -2.04 (s,3H,0-C-CH3) ^ 3.70 (s, 3H,-C-OCH3) 3. 98,) 4.18 (AB part of an ABX pattern, 2H,-CH2-OAc,JAB=10 Hz, Hz, J f i X=5 Hz) } :6.22 (S,1H,vinyl proton); m.p. 62-64°C. Anal. Calcd. f o r C,-,H_,Oc: C, 66.21; H, 7.84. Found: C, 65.96; 1 / 24 D H, 8.00. -162-C i s - k e t o a c e t a t e (156), i . r . (film) X 1740, 1720 cm 1 ( e s t e r c a r b o n y l s ) , 1670 cm 1 (conj. c a r b o n y l ) ; p.m.r. 6=1.27 ( s, 3H, t e r t i a r y methyl) 0 . 90 ( s, 3H, t e r t i a r y methyl) , 2.04 (s,3H,OC-CH 3) , 3.70 ( s, 3H,COCH_3) 4.30 , 3.91 (AB p a r t of an ABX p a t t e r n , 2H ,-CH2-QAc , p o o r l y r e s o l v e d ) y -6 . 22 ( s , l H , v i n y l H). A n a l . C a l c d . f o r c i 7 H 2 4 ° 5 : C ' 66.21; H r 7.84. Found: C, 66.49; ' H, 7.80. PREPARATION OF KETAL ACETATE (160) OAc .60) To a stirred solution of lithium bromide (18.Og, 0.21mole) i n 250 ml of HMPA under an atmosphere of nitrogen at 60 qC was added (5.Og,17.4mmol) of a mixture of octalones (155) and (156) . The reaction mixture was then heated at 140-150°C while nitrogen was bubbling through the solution. The reaction flask was then cooled to room temperature and water added to dissolve the excess lithium bromide. The reaction mixture was extracted with petroleum ether (7x50ml) and the combined extracts were washed with water (5x100ml) , brine (2x100ml), dried (MgSO^ ) and evaporated to yi e l d a crude o i l . G.L.C. analysis indicated that the crude mixture contained three compounds. D i s t i l l a t i o n under reduced pressure afforded (3.4g, 79%) of decarbomethoxylated material as a mixture of three compounds; b.p. 140-155°C (bath temperature) at 0.35mm. -163-H T h i s l a t t e r mixture, was s u b j e c t e d to k e t a l i z a t i o n con-d i t i o n s w i thout f u r t h e r p u r i f i c a t i o n . ' A s o l u t i o n of the above mixture (6.8g, 27itmol) , diethylene glycol (2.5g, 4Qmmol), and a c a t a l y t i c amount of p - t o l u e n e s u l f o n i c a c i d i n 150 ml o f benzene was r e f l u x e d f o r 20 hours u s i n g a Dean-Stark apparatus. The r e a c t i o n mixture was then c o o l e d to room temperature, washed w i t h sodium b i c a r b o n a t e , water, d r i e d (MgS0 4) and evaporated to y i e l d crude k e t a l a c e t a t e (160). D i s t i l l a t i o n under reduced p r e s s u r e a f f o r d e d (7.0g, 87%) of pure ketal acetate (160); b.p. lSO-ieO^ (bath temperature) at 0.3mm. Upon cooling,the ketal acetate (160) crystallized. Recrystallization from petroleum-ether./ ether afforded white crystals of ketal acetate (160); m.p. 101-102°C; i . r . ( C H C I 3 ) \ 1725 cm"1 (ester carbonyl) ; -164-(160) p.m.r. <$=4.0 lm, 2H,-CH2-OAc), 3.92 (s , 4H,ethylene ketal H) , 2.00 (s,3H,OC-CH3) '1.03 (s,3H,tertiary methyl) ^ 0.87 (s,3H, t e r t i a r y methyl) . Anal. Calcd. for C,_H„0.: C, 69.36; H, 8.90. Found: C, X / z b 4 69.19; H, 8.83. PREPARATION OF KETAL ALCOHOL (161) (161) To a mixture of lithium aluminum hydride (10 eq) -165-in freshly d i s t i l l e d THF (250 ml) was added dropwise (5.0g,_ 16.7mmol) of ketal acetate (16 0) i n 50 ml of THF. The solution was refluxed for 1.5 hours and cooled to room temperature. The reaction was quenched by the careful (portion wise) addition of sodium sulfate de cany dr ate ..'Addition was continued until the excess lithium aluminum hydride was destroyed. The res u l t i n g mixture was f i l -tered through c e l i t e and thoroughly washed with ether. The f i l t r a t e was dried (MgSO^) and evaporated to give crude ketal alcohol (161) .Distillation under reduced pressure afforded (4.0g, 94%) of ketal alcohol (161); b.p. 150-155°C (bath temperature) at 0.15 mm; i . r . (film) y _ 3325 cm"1 (hydroxyl); p.m.r. 6=3.94 (S»4H, AIua X ethylene ketal H) , 3.70 (m,2H,-CH2-OH) } 1.03 (s,3H,tertiary methyl) 0.83 ( s, 3H, t e r t i a r y methyl) . Mol. Wt. calcd. for C 1 5 H 2 4 ° 3 : 252.1725. Found (high resolution mass spectrometry) 252.1697. PREPARATION OF KETAL TOSYLATE (162) ( 1 6 2 ) To a solution of ketal alcohol (161) ( 4.0g, 15.8 mmol) in 50 ml of p y r i d i n e was added 1.5 e q of f r e s h l y r e c r y s t a l l i z e d p - t o l u -e n e s u l f o n y l c h l o r i d e . The r e a c t i o n was l e f t t o stand a t room temperature f o r 12 hours, poured i n t o ice-water ( 2 0 0 ml), s t i r r e d f o r 1 5 minutes, and taken up i n e t h e r . The combined et h e r ex--166-tracts were washed with cold (IN) hydrochloric acid, water, dried (MgSO^) and evaporated at room temperature under reduced pressure to y i e l d a pale yellow o i l . The crude o i l was dissolved in a minimum amount of petroleum ether, cooled to -78°C, and the flask etched to induce c r y s t a l l i z a t i o n . R e c r y s t a l l i z a t i o n from petroleum ether/acetone afforded 6.5 g ()99%) of pure ketal tosylate (162) as white needles,- m.p. 100-101°C; i . r . (CHC1,) x 1 1 9 0 cm"1 (doublet); p.m.r. 6 =7. 38 , 7. 82 (d,d, 4H,aromatic protons, J=8.5 Hz)^ 3.80-4.20 (complex m,2H,-CH2-CTs) , 3.9 6 (s,4H, ethylene ketal H), ~2.45 ( s, 3H , aromatic methyl), 0.9 8 ( s, 3H,tertiary methy1) , 0.81 ( s, 3H, t e r t i a r y methyl). Anal. Calcd. for C 2 2H 3 Q0 5S: C, 65.01; H, 7.44; S, 7.88. Found: C, 6 5.18; H, 7.40; S, 7.97. PREPARATION OF KETO TOSYLATE (163) (163) To a solution of (6.4g, 15.7mmol) of keto tosylate (163) in 125 ml of acetone and 30 ml o f water was added dropwise, 2 ml of c o n c e n t r a t e d s u l f u r i c a c i d . The r e a c t i o n mixture was l e f t to s t i r f o r 0.75 hours at 50° C then poured into a s t i r r i n g solution of s a t u r a t e d aqueous sodium b i c a r b o n a t e . The r e s u l t i n g mixture was e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were -167-washed with water u n t i l neutral, dried (MgSO^) and evaporated under reduced pressure at room temperature to give a crude yellow o i l . High vaccuum evaporation removed the l a s t traces of solvent to y i e l d (5.6 g , 99% ) of keto tosylate (163) } i . r . (film) XiTiax 1720 cm - 1 (sat. carbonyl); p.m.r. 6 =7.28, 7.70 (d,d,4H, aromatic protons, J=8.0 Hz), 3.8 ( m, 2H,-CH2-CTs 2.3 (s,3H, aromatic methyl), 0.90 (s, 3H, t e r t i a r y methyl), 0.72 (s , 3H , t e r t i a r y methyl). PREPARATION OF OCTALONE (165) (165) To a solution of potassium t-butoxide (2.5 eq) (pre-pared from .616 g of potassium i n 50 ml of t-butyl alcohol followed by evaporation of the t-butyl alcohol), i n 50 ml of freshly d i s t i l l e d HMPA, was added dropwise, under an atmosphere of nitrogen, (2.3g, 6.3mmol) of keto tosylate (163) in 50ml of HMPA. After addition was complete the reaction was s t i r r e d an additional 10 minutes and quenched by the addition of water and 3N HCl. The res u l t i n g mixture was extracted (5x50 ml) with petroleum ether. The combined ether extracts were washed (7x50 H 20), dried (MgSO^) and evaporated to y i e l d yellowish wet c r y s t a l s . Short path d i s t i l l a t i o n -discarding material that d i s t i l l e d below 70°C and above 120°C- afforded 655mg of a colourless o i l ; b.p. 95-110°C (bath -16 8-tenperature ) at 0.015 mm. Chromatography on s i l i c a gel of the low b o i l i n g material and residue afforded an additional 157 mg of a crude yellow o i l . Short path distillation of the latter yielded an additional (78mg, 4%) of octalone (165). Upon cooling , the octalone (165) crystallized. Recrystallization from petroleum ether/ether afforded (733mg, 64%) of octalone (165); m.p. 63-64°C; i . r . (CHC1.,) X 1670 cm"1, 1640 cm"1 (ct,B unsaturated j ITlclX carbonyl); p.m.r. S= 5.72 (s, IH, vinyl), 6= 1.36 (s, 6H, 2 quaternary methyls); u.v. y 238 (e 13,000); max Mol. Wt. Calcd. for C]_3 H^3 0 : 190.1361. Found (high resolution mass spectrometry) 190.1357. PREPARATION OF DIENONE (16 6) (166) To a s t i r r e d solution of octalone (165) 70 ml of dioxane, was added 3 ml of a c e t i c a c i d and 1.5 eq of 64 DDQ (666 mg). The solution was refluxed for 17 hours, cooled and f i l t e r e d through a bed of c e l i t e (1"). The f i l t r a t e was evaporated and the residue was extracted with ether. The com-bined ether extracts were washed with H 20, sodium bicarbonate, E^O u n t i l neutral, passed through a 1" layer of a c t i v i t y III alumina, dried (MgSO^) and evaporated to y i e l d crude dienone (166). High vacuum d i s t i l l a t i o n afforded . ( 0.285g , 60%) 0 f c r y s t a l l i n e -169-dienone (166). Recrystallization from petroleum ether afforded pure crystals of dienone (166); m.p. 72-73°C; i . r . (CHC1J A 1660 cm-1, 1630 cm-1, 1601'cm"1 (due to cross conjugated carbonyl); p.m.r. 6= 7.02 (d, IH, J"2 3=10Hz, vinyl) 6=6.30 (d of d, IH, J1 2=2Hz, J 3 2=10Hz, vinyl), 6=5.99 (d, IH, J 2 ^2Ez) , 6=1.11 (s, 3H, quaternary methyl), 6=1.06 (s, 3H, quaternary methyl); u.v. u 247 ( e= 14,700) Anal. Calcd. for C^^O: C, 82.94; H, 8.57. Found: C, 82.65; H, 8.50. PREPARATION OF OCTALONE (167) (167) To a s t i r r e d solution of cuprous iodide (Q.861g, 0.425 mmol) i n 15 ml of ether at 0°C under an atmosphere of nitrogen was added 5.3 ml of 1.7 M methyl lithium. This mixture was then s t i r r e d an addit i o n a l 10 minutes at 0°C. A solution of dienone (166) (0.425 g; 2.26 mmole) i n 15 ml of ether was then added over a period of 10 minutes. Afte r s t i r r i n g at 0°C f o r 1 hour, the reaction was quenched by the slow addition of a saturated solution of ammonium chloride. The solution was s t i r r e d for 20 minutes, transferred to a separatory funnel, d i l u t e d with 100 ml of water and thoroughly extracted with ether. The combined ether extracts were washed with water, brine, dried (MgSO.), and evaporated to y i e l d a crude yellow o i l . D i s t i l l a --170-tion under reduced pressure afforded (0.375g,0.45mole)of octalone (167). A n a l y t i c a l sample collected on 10% O.V. 17 c r y s t a l l i z e d ^ m.p. 63-64°C; i . r . (CHCl 3) A m a x 1650, 1640 cm - 1 (conj. carbonyl); p.m.r. 6=5.72 (s,lH, v i n y l H), 1.12 ( s, 3H, t e r t i a r y methyl) , 1.08 (s,3H,tertiary methyl) } 1.02 (d,3H,secondary methyl) . Anal. Calcd. for C l 4H 2 Q0: C, 82.30; H, 9.87. Found: C, 81.98; H, 10.00. PREPARATION OF DIENONE (169) To a solution of octalone (167) (0.325g, 1.51 mmol) in 50 ml of THF , containing 2 ml of acetic acid at 45°C under an atmosphere of N 2, was added 0.576 g (1.1 eq) of pyridinium hydrobromide perbromide . The solution was l e f t to s t i r for one hour, cooled, neutralized with sodium bicarbonate, and extracted with ether. The combined ether extracts were washed with water, dried (MgSO^) and evaporated to y i e l d the crude bromo-ketone ( 100%). The crude bromoketone (0.457 g, 1.61 mmole) was dissolved i n 50 ml of DMF containing 0.490 g (3.5 eq) of lithium bromide and 0.420 g (3.5 eq) of lithium carbonate and refluxed for 3 hours . The reaction mixture was then cooled, d i l u t e d with water and extracted with petroleum ether. The combined organic extracts were washed with water, brine, dried (MgSO.) -171-and evaporated to y i e l d 0.307 g of a crude mixture. D i s t i l l a -t i o n under reduced pressure afforded .240 g of a yellow o i l ; b.p. 135-140°C (bath temperature) at 0.2mm. G.L.C. analysis indicated three major compounds. Chromatography of this mixture on s i l i c a gel afforded with gradient elution using a mixture of petroleum ether-ether 67 mg of s t a r t i n g material (octalone (167)), 70 mg of bromo-dienone (168) as a c r y s t a l l i n e compound, and (lOOmg, 40%) of pure dienone (169) ; i . r . (film) X m = v 1660, 1630 cm - 1 (cross conj. carbonyl); p.m.r. 6=6.00 (d,lH,vinyl H, J=2 Hz) ,6.14 (d of d,lH, v i n y l H, J=2 Hz),, 2.00 (d,3H,vinyl methyl, J=2 Hz), 1.12 ( s, 3H, t e r t i a r y methyl) / 1. 20 (s,3H, t e r t i a r y methyl) . Mol.Wt. Calcd. for C 1 4H l nO: 202.1357. Found (high resolution mass spectroscopy), 202.1321. PREPARATION OF OCTALONE (124) (124) To a solution of cuprous iodide (5 eq) i n 5 ml of ether at 0°c under an atmosphere of N 2 was added (5 eq) of methyl lithium and the solution was l e f t to s t i r at 0°C for 10 minutes. A solution of cross conjugated dienone (164) (30mg, O..144mmol) in 2ml ether was then added dropwise and the reaction was left to stir for 5 hours at room temperature. The reaction was then quenched by the dropwise addition of a saturated solution of ammonium chloride. -17 2-The solution was stirred for 20 minutes, transferred to a separatory funnel, diluted with water, and thoroughly extracted with ether. The combined ether extracts were washed with water, brine, dried (MgSO^ ) and evaporated to yield a crude o i l . Chromatography of the crude o i l on s i l i c a gel afforded with * gradient elution using a mixture of petroleum ether/ ether (7mg,40%) of crystalline octalone (124); m.p. 53-54°C; p.m.r. 6= 5.7 (s, IH, vinyl) 6=1.14 (s, 3H, tertiary methy), 6=1.09 (s, 3H, tertiary methy), 6=1.05 (s, 3H tertiary methyl), 6=1.00 (s, 3H, tertiary methyl). Low resolution mass spectroscopy showed parent peak mass as 218. Mol. Wt. Calcd. for C^5 H22 0 : 2 l 8 - l 6 7 0 » Found (high resolution mass spectrometry) 218.1692. PREPARATION OF KETO CYANIDE (172) Following the procedure of Nagata et al , (method B) , dienone (166) was treated with a six fold excess of diethyl aluminum cyanide in benzene (2.1M) at room temperature for two hours under an atmosphere of nitrogen. The reaction mixture was then poured into a 2N NaOH- solution and extracted with dichloromethane and the crude product was purified by preparative T.L.C.. The sample had spectral properties in accord with structure (172); i . r . A 2250 cm-1, 1670 cm-1 ( conj. carbonyl); p.m.r. 6= 5.86 (s, IH, vinyl proton), 6=3.32 (t, IH, -CH-CN, J=3.5 Hz ), Yield based on recovered starting material (14mg) . -173-2.68 (d,2H,J=3.5 Hz), 6 = 1.16 (<;, 3H,tertiary methyl) , 6=1.20 ,3H,tertiary methyl). f -174-REFERENCES 1. S.K. Malhotra and H.J. Ringold, J. Am. Chem. Soc. 86, 1997(1964). 2. H.O. House,Modern Synthetic Reactions, (2nd Ed.) , Benjamin, New York, N.Y. 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